CLASSES

Vitamin K Antagonists

DEA CLASS

Rx

DESCRIPTION

Coumarin anticoagulant widely used to prevent and treat thromboembolic disease; the S-isomer 3-5 times more potent than R-isomer; major hemorrhagic risks have decreased due to the adoption of INR method of monitoring and decreasing the intensity of anticoagulation for most indications; observe for drug interactions.

COMMON BRAND NAMES

HOW SUPPLIED

DOSAGE & INDICATIONS

For general dosing information in patients requiring warfarin anticoagulation. NOTE: Clinical practice guidelines recommend against the routine use of pharmacogenetic testing for guiding dosing in patients initiating warfarin therapy.

Oral or Intravenous dosage

Adults without known risks for enhanced INR response to warfarin

2—5 mg PO/IV once daily. Typical maintenance doses are 2—10 mg PO/IV once daily. Clinical practice guidelines recommend 10 mg PO once daily for the first 2 days for patients healthy enough to be treated as outpatients.

Initially, <= 5 mg PO/IV may be appropriate to reduce the risk of excessive INR elevation and potential bleeding events.

Adults who have undergone heart valve replacement

Initially, 2—3 mg PO/IV may be appropriate to reduce the risk of excessive INR elevation and potential bleeding events. These patients have a higher sensitivity to warfarin probably due to effects of cardiopulmonary bypass and concomitant therapies.

Adults with VKORC1 variant GG and CYP2C9 variant *1/*1 or *1/*2

Initially, 5—7 mg PO/IV once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants.

Initially, 3—4 mg PO/IV once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants. Patients with these CYP2C9 variants may require more prolonged time (> 2—4 weeks) to achieve maximum INR effect for a given dosage regimen.

Adults with VKORC1 variant AG and CYP2C9 variant *1/*1

Initially, 5—7 mg PO/IV once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants.

Initially, 3—4 mg PO/IV once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants. Patients with CYP2C9 *1/*3 or *2/*2 may require more prolonged time (> 2—4 weeks) to achieve maximum INR effect for a given dosage regimen.

Adults with VKORC1 variant AG and CYP2C9 variant *2/*3

Initially, 0.5—2 mg PO/IV once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants. Patients with this CYP2C9 variant may require more prolonged time (> 2—4 weeks) to achieve maximum INR effect for a given dosage regimen.

Adults with VKORC1 variant AA and CYP2C9 variant *1/*1 or *1/*2

Initially, 3—4 mg PO/IV once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants.

Initially, 0.5—2 mg PO/IV once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants. Patients with these CYP2C9 variants may require more prolonged time (> 2—4 weeks) to achieve maximum INR effect for a given dosage regimen.

Adults with VKORC1 variant AA, AG, or GG and CYP2C9 variant *3/*3

Initially, 0.5—2 mg PO/IV once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants. Patients with this CYP2C9 variant may require more prolonged time (> 2—4 weeks) to achieve maximum INR effect for a given dosage regimen.

Neonates, Infants, Children, and Adolescents

Initially, 0.2 mg/kg PO/IV once daily for 2 days. For patients with impaired liver function, use a lower initial dose. A maximum dosage for warfarin has not been defined; however, most adult patients are maintained on doses ranging from 2—10 mg/day. Weight-based dosage requirements for warfarin have been determined to be age-dependent. In a large cohort of pediatric patients (n = 262), infants required an average daily dose of 0.32 mg/kg while adolescents required an average daily dose of 0.09 mg/kg to maintain INR 2—3.

For the treatment and further prevention of deep venous thrombosis (DVT) or pulmonary embolism (PE) after the initial, acute phase of treatment.

Conventional, moderate-intensity (INR 2—3) anticoagulation.

Oral dosage

Adults

Treatment with warfarin should be started on the same day as heparin, low molecular weight heparin (LMWH), or fondaparinux and continue for >= 5 days and until the INR is >= 2 for >= 24 hours. Warfarin should be continued for 3 months in most patients, including patients with a proximal DVT or PE that is provoked by surgery or nonsurgical transient risk factor. Patients with an unprovoked PE or DVT of the leg should be treated for >= 3 months if the risk of bleeding is low or moderate and for 3 months if there is a high bleeding risk. For patients with venous thromboembolism associated with active cancer, treatment should continue for > 3 months. In patients who receive extended treatment (i.e., > 3 months), the same anticoagulant should be used as the first 3 months and continuation of therapy should be assessed at periodic intervals. Patients with activated protein C resistance should probably receive indefinite treatment if they have recurrent disease, are homozygous for the gene, or have multiple thrombophilic conditions.

Low-intensity† (INR 1.5—1.9), long-term† anticoagulation.

Oral dosage

Adults

Clinical practice guidelines recommend against low-intensity anticoagulation with warfarin (INR 1.5—1.9). During an early investigative trial (PREVENT), a target lower-intensity INR range of 1.5—2 long-term was evaluated vs. placebo in patients previously treated for about 6 months following DVT. The average duration of warfarin therapy was 2.1 years (maximum 4.3 years). This study was stopped early due to statistically reduced rate of VTE in the low-intensity anticoagulation group. A subsequent trial (ELATE) demonstrated that conventional-intensity (INR 2—3) warfarin therapy is more effective than low-intensity (INR 1.5—1.9) warfarin therapy for the long-term prevention of recurrent VTE in patients previously treated with >= 3 months of warfarin therapy. In addition, the ELATE trial did not show the reduced risk of clinically important bleeding that was expected with the low-intensity warfarin regimen.

For deep venous thrombosis (DVT) prophylaxis.

For DVT prophylaxis in patients undergoing total hip or knee replacement surgery or hip fracture surgery.

Oral or Intravenous dosage

Adults

A target INR of 2.5 (range 2—3) is recommended by clinical practice guidelines. For patients who are not candidates for injections or an intermittent pneumatic compression device (IPCD), adjusted-dose warfarin is an alternative to the preferred regimen, low molecular weight heparin, or secondarily, apixaban or dabigatran, as antithrombotic prophylaxis for patients undergoing total hip or knee replacement surgery or hip fracture surgery. Warfarin should be started preoperatively or the evening of the surgery. Dual prophylaxis with pharmacologic therapy and IPCD is encouraged for the duration of the hospital stay. Pharmacologic therapy should continue for a minimum of 10—14 days after surgery; up to 35 days is recommended.

For coronary artery thrombosis prophylaxis in high or very high-risk patients with stable angina† or chronic coronary artery disease†.

Oral dosage

Adult males at high-risk for cardiovascular events

Low-intensity warfarin (target INR 1.5) has been recommended in men at high risk of cardiovascular events in the prevention of those events and for reduction of overall mortality.

Adult males at very high-risk for cardiovascular events

The combination of low-dose aspirin (75—80 mg/day) and low-intensity warfarin (target INR 1.5) may be considered over either agent alone for the prevention of cardiovascular events and reduction in mortality for men at very high-risk for such events.

For thrombosis prophylaxis in patients with atrial fibrillation.

Oral or Intravenous dosage

Adults

A target INR of 2.5 (range: 2—3) is recommended. A case-control study found that INR levels > 2 added little efficacy, while the risk of stroke increased at INR levels < 2. The odds of stroke increased even more dramatically if the INR was < 1.5. Long-term warfarin therapy should be considered for all patients with atrial fibrillation with a high risk factor (e.g., previous TIA, stroke or systemic embolism; those with poor left ventricular function; rheumatic mitral valve disease ; prosthetic heart valve; age >= 75 years; or those with hypertension. A target INR of 3 (range: 2.5—3.5) is recommended for atrial fibrillation patients with tilting disk valves or bileaflet mechanical valves in the mitral or aortic position. Patients with one moderate risk factor (e.g., age 65—75 years, diabetes mellitus, or coronary artery disease with preserved LV function) should be treated with warfarin or aspirin therapy long-term. Patients with no high-risk or moderate-risk factors and no clinical or echocardiographic evidence of cardiovascular disease should be treated with aspirin.

For thrombosis prophylaxis in patients with atrial fibrillation or atrial flutter who are undergoing cardioversion.

Oral dosage

Adults

Warfarin with a target INR of 2.5 (range 2—3) 3 weeks before and >= 4 weeks after the procedure. Warfarin should be continued until normal sinus rhythm has been maintained for >= 4 weeks. Patients who have had AF for < 48 hours should be offered anticoagulation during the peri cardioversion period.

For thrombosis prophylaxis in patients with prosthetic heart valves.

Oral or Intravenous dosage

Adults with bioprosthetic heart valves

Clinical practice guidelines recommend a target INR of 2.5 is recommended for the first 3 months after valve insertion. After 3 months, aspirin 75 to 100 mg PO daily is recommended. Therapy for as long as 6 months may be considered for up to 6 months in patients who have had aortic valve insertion. Patients with risk factors for thromboembolism (e.g., atrial fibrillation) should receive lifelong warfarin therapy.

If possible, avoid the use of warfarin during the first trimester of pregnancy and near term. As an alternative to adjusted-dose heparin or adjusted-dose LMWH throughout the pregnancy, warfarin may be initiated after the 13th week of pregnancy. Heparin or LMWH should be resumed close to delivery (Grade 1A Recommendation). In women who are high risk for thromboembolism (e.g., older generation prosthesis in the mitral position or history of thromboembolism), warfarin may be used throughout the pregnancy and replaced with heparin or LMWH close to delivery; low-dose aspirin (75 to 100 mg/day) also is recommended (Grade 2C Recommendation). Long-term anticoagulation should be resumed postpartum when hemostasis is assured. Other practice guidelines suggest warfarin plus aspirin 75 to 100 mg PO daily may be used during the first trimester in patients who can achieve therapeutic INR with doses of 5 mg/day or less with frequent monitoring and only after full discussion of the risks and benefits of warfarin therapy during the first trimester of pregnancy.

Discontinue warfarin therapy at the time of initial presentation until the need for invasive procedures are ruled out and the patient has been stabilized without signs of central nervous system involvement. Warfarin can be reinstituted when the patient is stable and has not contraindications for therapy or neurologic complications.

For thrombosis prophylaxis in patients with mechanical prosthetic heart valves and a history of bleeding while receiving warfarin therapy.

Oral dosage

Adults

Every effort should be made to maintain the INR at the lower limit of the therapeutic range (See standard dosage guidelines for prosthetic heart valve patients). For patients with a mechanical prosthetic heart valve and a persistent risk of increased bleeding, the anticoagulant intensity can be reduced to an INR of 2—2.5.

For stroke prophylaxis in patients with cerebral venous sinus thrombosis (CVST) after primary treatment with heparin or LMWH.

Long term warfarin therapy (INR target 2.5, range 2—3) is recommended unless venous interruption or PFO closure is considered preferable therapy. In selecting therapy, consider the possibility of paradoxic embolism and systemic embolism from the arterial side of the aneurysm.

For stroke prophylaxis in patients with dilated cardiomyopathy (DCM), particularly in the subgroup of patients with concomitant atrial fibrillation or with a prior history of systemic embolization.

Oral dosage

Adults

The use of anticoagulation in patients with dilated cardiomyopathy (DCM) is controversial. In patients with concomitant atrial fibrillation or with a prior history of systemic embolization, a target INR of 2—3 has been recommended. Not recommended for patients with DCM and no coexisting risk factors.

The use of warfarin following myocardial infarction (MI) is controversial. After MI, warfarin may be used to reduce the risk of systemic or pulmonary embolism in high-risk patients such as those with anterior Q-wave infarction, AF, severe LV dysfunction, or congestive heart failure. The optimal antithrombotic regimen for long-term management in patients post-MI has not been established. A recent guide to warfarin therapy provides three potential strategies for antithrombotic therapy following MI: 1) aspirin alone, 2) aspirin plus moderate-intensity (INR 2—3) warfarin, or 3) high-intensity (INR 3—4) warfarin alone. The ASPECT-2 study reported reduced cardiovascular events and deaths with high-intensity (INR 3—4) warfarin or moderate-intensity (INR 2—2.5) warfarin plus aspirin 80 mg/day compared to aspirin alone (80 mg/day). In a similar trial, WARIS II, compared warfarin (INR 2.8—4.2), aspirin 75 mg/day, or aspirin 75 mg/day plus warfarin (INR 2—2.5), initiated at discharge post-MI. Consistent with the ASPECT-2 trial, the WARIS II warfarin regimens are more effective in reducing composite events (death, MI, stroke) vs. aspirin alone, but have a higher rate of bleeding and require greater monitoring. Further study is needed to evaluate other strategies such as aspirin plus low-intensity warfarin (INR < 2) or monotherapy with moderate intensity warfarin (INR 2—3). Previously, in the ASPECT-1 study comparing oral anticoagulation to placebo, patients given anticoagulants were less likely to suffer a recurrent MI; however, since the benefits were not better than studies of aspirin and since the risk of bleeding complications is greater with oral anticoagulants, many clinicians traditionally prescribed aspirin in this setting. According to previous guidelines in 2001 by the American College of Chest Physicians (ACCP), aspirin has been recommended over warfarin for long-term therapy in patients with a low risk of embolism. Warfarin therapy (target INR of 2.5 (range: 2—3) for <= 3 months) has been recommended in the clinical setting of increased embolic risk or if aspirin or when other anti-platelet therapy is contraindicated. Warfarin should be continued indefinitely in patients with atrial fibrillation. Some patients with recurrent ischemic episodes following acute MI may benefit from a combination of warfarin and aspirin. Treatment with low-dose aspirin and low-intensity warfarin (target INR of 1.5) has been suggested.

For the coronary artery thrombosis prophylaxis in patients with unstable angina†.

Oral dosage

Adults

Patients who have contraindications to aspirin, ticlopidine, and clopidogrel should receive heparin, followed by warfarin (INR 2—3) for a period of several months. Aspirin in combination with therapeutic anticoagulation (heparin for the first 3—4 days after the onset of acute unstable angina followed by warfarin for up to 12 weeks) was found to be superior to aspirin alone in 214 patients with unstable angina. In this study, therapy was initiated within a mean of 9.5 hours of qualifying pain and warfarin was dosed to achieve an INR of 2—3. NOTE: ACCP guidelines recommend against routine use of warfarin after percutaneous coronary intervention (PCI) unless there is a specific indication for systemic anticoagulation.

For prophylaxis of arterial and/or venous thromboembolism in patients with antiphospholipid antibody syndrome.

DOSING CONSIDERATIONS

Hepatic Impairment

Although specific guidelines for dosage adjustment are not available, patients with hepatic impairment may require a lower dosage of warfarin due to decreased warfarin metabolism and decreased production of coagulation factors.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

ADMINISTRATION

Oral Administration

Administer dose at the same time every day. May be taken with or without food; food decreases the rate but not the extent of absorption.

Equivalent intravenous and oral doses of warfarin produce similar plasma concentrations.The administration of intravenous warfarin does not provide any increased biological effect or earlier onset of action compared to oral dosing, therefore IV therapy is usually reserved for those patients who cannot absorb warfarin via the oral route.

Reconstitution:Reconstitute 5 mg vial with 2.7 ml of sterile water for injection to yield a final concentration of warfarin 2 mg/ml.Following reconstitution, the solution is stable for 4 hours at room temperature. However, the solution does not contain a preservative; any unused portion should be discarded.

Intravenous injection:Inject slowly over 1—2 minutes into a peripheral vein.

STORAGE

CONTRAINDICATIONS / PRECAUTIONS

Coumarin anticoagulants hypersensitivity

Warfarin should be used with caution in patients with a history of coumarin anticoagulants hypersensitivity. Consensus on whether or not cross-sensitivity between warfarin and other coumarin anticoagulants such as dicumarol, acenocoumarol, or phenprocoumon occurs is not available as both cross-sensitivity on rechallenge with a different coumarin anticoagulant and successful use of a different coumarin anticoagulant has been described. A case report also describes the successful initiation of long-term anisindione (an indanedione anticoagulant) in a patient with a history of maculopapular rash to warfarin. Although no longer commercially available in the US, patients with a history of hypersensitivity to dicumarol or other coumarin anticoagulants should be monitored closely for hypersensitivity reactions including maculopapular skin eruptions or pruritus if warfarin is initiated.

Warfarin can cause major or fatal bleeding. Warfarin is contraindicated in patients with conditions in which therapy with warfarin may result in uncontrolled bleeding including hematological disease; GI bleeding, genitourinary bleeding, respiratory tract bleeding, retinal bleeding, or intracranial bleeding; head trauma; hemorrhagic stroke; aneurysm; aortic dissection; pericarditis or pericardial effusion; bacterial endocarditis; threatened abortion; eclampsia and preeclampsia; recent or planned surgery of the central nervous system, eye, or following trauma that results in large open surfaces; diagnostic or therapeutic procedures with potential for uncontrolled bleeding including epidural anesthesia, spinal anesthesia, spinal puncture and lumbar puncture; and malignant hypertension. Due to the risk of bleeding, warfarin should be used only with extreme caution in patients with hemophilia, leukemia, peptic ulcer disease, and polycythemia vera. Usually, warfarin therapy is stopped 4—5 days prior to surgery. In patients with an intermediate- or high-risk for thromboembolism, give either heparin or low molecular weight heparin (LMWH) as the INR falls. Administration of vitamin K 24—48 hours prior to surgery will shorten the duration of heparin or LMWH prior to surgery; however, it may make it more difficult to reinstitute warfarin anticoagulations. In situations with a low risk of bleeding, another option is to lower the dose of warfarin and operate at an INR of 1.3—1.5. This INR level has shown to be safe in randomized trials of gynecologic and orthopedic surgery patients. A severe elevation (> 50 seconds) in activated partial thromboplastin time (aPTT) with a PT/INR in the desired range has been identified as a risk factor for postoperative hemorrhage. Warfarin should be used cautiously in the following conditions because bleeding, should it occur, would be extremely serious during warfarin therapy: vasculitis; polyarthritis; moderate to severe hypertension; or indwelling catheters. The risk of major bleeding with warfarin therapy is increased during the drug initiation phase, in older patients >= 65 years of age, in patients with highly variable INRs, in patients requiring long-term treatment, in patients with certain genetic polymorphisms of CYP2C9 and/or VKORC1, and in patients with a history of cerebrovascular disease (e.g., stroke), GI bleeding, atrial fibrillation, or in the presence of serious comorbid conditions such as cardiac disease, malignancy (neoplastic disease), renal disease including renal impairment or renal failure, or anemia. An INR > 4 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. High-intensity oral anticoagulations (INR 3—4.5) is associated with an unacceptable incidence of intracranial hemorrhage when used in patients with cerebral ischemia of presumed arterial origin (e.g., patients with recent TIA or minor ischemic stroke). Warfarin therapy must be individualized for the patient. Warfarin has a narrow therapeutic range and may be affected by factors such as other drugs, dietary vitamin K (see Drug Interactions), and other disease states. Warfarin dosage should be controlled by periodic monitoring of the INR or other suitable coagulation tests; consideration should be given for more frequent monitoring in patients that have risk factors for major bleeding. Determination of whole blood clotting or bleeding times are not effective measures to monitor warfarin therapy. Monitor INR response and for signs of bleeding during warfarin therapy. ACCP guidelines for managing elevated INR and/or serious bleeding in adult patients are detailed in the dosage section (see Dosage section for Therapeutic Drug Monitoring).

Asian patients

Patients with genetic polymorphisms of CYP2C9 and VKORC1 may require lower maintenance dosages of warfarin as compared to patients without these polymorphisms; more frequent monitoring of the INR may also be necessary. Differences in the frequencies of these variant alleles in people with different ethnic backgrounds exist; for example, in Caucasians, the frequency of the CYP2C9*2 variant is 8—20%, while the frequency of the CYP2C9*3 variant is 6—10%. In Blacks, the frequencies are 2—4% and 1—2% for the presence of CYP2C9*2 or CYP2C9*3 variant alleles, respectively. In Asians, the CYP2C9*2 variant allele does not occur, and the frequency of the CYP2C9*3 variant allele is 1—4%. Similarly, ethnicity plays a role in the presence of polymorphisms in the VKORC1 gene. There are several VKORC1 variants that are known to affect warfarin dosing including -1639G>A, 1173C>T, and 3730G>A. Approximately 82%, 89%, and 13% of Asian patients carry variants in these alleles, respectively. In contrast, approximately 14%, 42%, and 45% of Caucasians, and 0%, 9%, and 49% of Blacks carry variants in these alleles, respectively. Around 30% of the variance associated with warfarin dosing can be attributed to the presence of a VKORC1 variant allele and 40% of the variance in dose can be attributed to the presence of both a CYP2C9 and a VKORC1 variant allele. This is supported by the fact that in Chinese patients, who express a high frequency of variant alleles of the VKORC1 gene, a relatively low maintenance dose of only 3.3 mg +/- 1.4 mg is necessary to achieve an INR of 2—2.5. Accordingly, the manufacturer of warfarin indicates that Asian patients may require lower initiation and maintenance doses of warfarin. The results of a meta-analysis comparing patients with CYP2C9 variant alleles to those without demonstrate that the daily warfarin dose is 17% lower in patients with at least one copy of the variant CYP2C9*2 allele (0.85 mg/day less, 95% CI 0.6—1.11 mg), 37% lower in patients with at least one copy of the variant CYP2C9*3 allele (1.92 mg/day less, 95% CI 1.37—2.47 mg), and 27% lower in patients with at least one copy of the variant CYP2C9*2 or CYP2C9*3 allele (1.47 mg/day less, 95% CI 1.24—1.71 mg). It should be noted that the studies in the meta-analysis enrolled primarily Caucasian patients. In a cross-sectional study, the presence of variant alleles in the CYP2C9 gene or the VKORC1 -1639 gene lead to lower daily maintenance doses of warfarin. Patients with CYP2C9*2 variants required the lowest daily dose, and patients with VKORC1 -1639 variant allele AA required the lowest daily dosage. In addition, patients with CYP2C9 variant alleles may be at increased risk of bleeding compared to patients without these genetic mutations; an increased risk of bleeding in patients with mutations in the VKORC1 gene has not been consistently demonstrated. Results from a meta-analysis indicate that the risk of bleeding (severity or type not defined) is increased in patients with at least one of the CYP2C9 variant alleles. In patients with at least one copy of the CYP2C9*2 variant allele, the relative risk of bleeding is 1.91 (95% CI 1.16—3.17); in patients with at least one copy of the CYP2C9*3 variant allele, the relative risk of bleeding is 1.77 (95% CI 1.07—2.91). Finally, in patients with a copy of either of the CYP2C9 variant alleles, the relative risk of bleeding is 2.26 (95% CI 1.36—3.75). Data from a study of both Black and Caucasian patients (48% Black) indicate that the presence of a variant allele in the CYP2C9 gene is associated with an increased risk of major hemorrhage, defined as life threatening or fatal bleeding (RR 3, 95% CI 1.1—8), but not minor bleeding, regardless of race. In this study, the presence of variant alleles in the VKORC1 gene did not increase the risk of minor or major bleeding. Currently, genetic testing for these polymorphisms is not recommended prior to initiating warfarin therapy. Several dosing regimens for the initiation of warfarin have been developed based on the presence of polymorphisms, concomitant use of interacting drugs, age, height, weight, and comorbid conditions in patients already stabilized on warfarin therapy. Such dosing regimens may be beneficial in patients to minimize adverse events, especially bleeding. However, these dosing regimens have not been validated in randomized clinical trials. Currently, the routine determination of the presence of genetic polymorphisms in patients initiating warfarin is not necessary; furthermore, in patients where genetic testing is desired, delaying warfarin initiation until the results are known is not recommended.

Dental work

In patients at high-risk of bleeding, warfarin should be discontinued prior to dental work. However, patients not at high-risk may continue warfarin therapy in most cases. During dental procedures that require local bleeding control, administer a mouthwash acid or aminocaproic acid mouthwash, without interrupting anticoagulant therapy.

Diabetes mellitus

Caution should be observed when warfarin is administered to patients at risk for tissue necrosis and/or gangrene (e.g. patients with diabetes mellitus). Anticoagulations therapy with warfarin may enhance the release of atheromatous plaque emboli, increasing the risk of complication from cholesterol microembolization. Discontinuation of warfarin recommended when this occurs.

Warfarin should be used with caution in patients with idiopathic thrombocytopenic purpura (ITP), heparin-induced thrombocytopenia (HIT) and deep venous thrombosis. The prothrombotic effects of HIT combined with the procoagulant effects of early warfarin therapy (reduced protein C activity) can result in complications including warfarin-induced skin necrosis and limb gangrene. Cases of venous limb ischemia, necrosis, and gangrene have occurred in these patients when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, amputation of the involved area and/or death occurred. Patients who develop limb gangrene while receiving warfarin often have a high INR (usually > 4) after starting warfarin therapy. The pathogenesis of warfarin-associated limb gangrene in patients with HIT appears to be insufficient protein C activity (has natural anticoagulant properties) to control the increased thrombin generation seen in these patients. Warfarin can be given safely if thrombin generation is adequately controlled with the use of danaparoid, hirudin, or argatroban, or if warfarin is initiated following resolution of the HIT. Warfarin should not be given alone or in combination with ancrod in patients with acute HIT.

Hepatic disease, including infectious hepatitis and cholestasis with symptoms of jaundice, potentiates the response to warfarin therapy by impairing the synthesis of coagulation factors or altering the metabolism of warfarin. Because chronic alcohol consumption may result in alcoholic liver disease (including cirrhosis), patients who chronically ingest large amounts of ethanol may have an enhanced response to warfarin therapy. In these patients, small doses of warfarin may cause a pronounced hypoprothrombinemic effect; thus, caution is required.

Intramuscular injections

Intramuscular injections of other drugs should be avoided if possible in patients receiving warfarin. IM injections may cause bleeding, bruising, or hematomas due to the anticoagulant effect of warfarin therapy. If required and appropriate for the administered drug, IM injections should be given to the upper extremities, which permits easy access for manual compression, inspection for bleeding, and use of pressure bandages.

Protein C deficiency, protein S deficiency

Patients with protein C deficiency or protein S deficiency can become transiently hypercoagulable when warfarin is initiated and may result in necrosis of the skin and underlying tissue. The risk associated with these conditions, both for recurrent thrombosis and for adverse reactions, is difficult to evaluate since it does not appear to be consistent for all patients. The initial symptom may be an intense burning in the affected area. Warfarin therapy should be immediately stopped because skin necrosis can be permanently disfiguring. If warfarin therapy is indicated in patients with protein C deficiency, anticoagulations should begin with heparin for 5—7 days to decrease the risk of tissue necrosis.

Vitamin K deficiency enhances the response to warfarin and may lead to an increased risk of bleeding. The effects of warfarin can be potentiated in patients with poor nutritional status and decreased vitamin K intake (especially if they are treated with antibiotics and IV fluids without vitamin K supplementation) or in states of fat malabsorption. In addition, patients with eating disorders such as anorexia nervosa or bulimia nervosa may have poor or fluctuating vitamin K intake.

Alcoholism, dementia, psychosis

Because safe use of warfarin in the outpatient setting depends on good patient compliance, warfarin is contraindicated in unsupervised patients with dementia, alcoholism, or psychosis.

Fever, hyperthyroidism, infection

Hypermetabolic states produced by fever or hyperthyroidism can increase the responsiveness to warfarin, probably by increasing the catabolism of vitamin K-dependent coagulation factors. Infection or disturbances of intestinal flora due to sprue or antibiotic therapy may alter responses to warfarin. Thus, warfarin therapy should be monitored closely in these situations.

Diarrhea, hyperlipidemia, hypothyroidism, peripheral edema

Numerous factors alone or in combination, including travel or changes in diet, environment, physical state, and medication may influence the response to warfarin. It is considered good practice to monitor the patient's response with additional PT/INR determinations in the period immediately after discharge from the hospital and whenever other medications are initiated, discontinued, or taken irregularly. The following conditions, alone or in combination, may be responsible for increased INR responses to warfarin: collagen vascular disease, diarrhea or steatorrhea, and neoplastic disease. Peripheral edema, hereditary coumarin resistance, hyperlipidemia, hypothyroidism and nephrotic syndrome, alone or in combination, have been associated with decreased responses to warfarin.

Tobacco smoking

Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, sudden tobacco smoking cessation may reduce the clearance and increase the therapeutic effects of warfarin despite the initiation of a nicotine replacement product. However, the decreased warfarin clearance may not always result in a clinically significant change in the PT or INR. Monitor to assess the need for warfarin dosage adjustment when changes in smoking status occur.

Geriatric

Geriatric patients are more susceptible to the effects of anticoagulants, possibly due to a decrease in the clearance of warfarin with age. Limited data suggests no difference in S-warfarin clearance and slightly decreased clearance of R-warfarin with increasing age. Therefore, lower doses of warfarin are usually required to produce a therapeutic level of anticoagulations. In addition, in a retrospective cohort of Medicare beneficiaries (mean age 79.4 years) receiving warfarin for atrial fibrillation, the use of long-term warfarin (>= 365 days) was associated with an increased risk of osteoporotic fracture (OR 1.25, 95% CI 1.06—1.48), especially vertebral fracture. However, when analyzed separately by gender, the increased risk of fracture was significant in men (odds ratio 1.63, 95% CI 1.26—2.1), but not women (OR 1.05, 95% CI 0.88—1.26). Furthermore, the risk of fracture was not increased in patients taking warfarin for < 1 year. Other independent predictors of fracture in this cohort of patients (regardless of length of warfarin therapy) were increasing age, high risk of falls, hyperthyroidism, neuropsychiatric disease, and alcoholism. Factors that were associated with a protective risk of fracture include African-American race, male gender, and the use of beta-adrenergic antagonists. Because the available alternative therapies (e.g., heparin, low molecular weight heparin) have also been associated with an increased risk of fracture, the authors of this study recommend that when prescribing warfarin to patients at risk of falling, patients should be encouraged to wear stable shoes, consume adequate amounts of calcium and vitamin D, exercise regularly, and use walking aids when necessary. In addition, unnecessary drugs should be discontinued.

Labor, obstetric delivery, pregnancy

Warfarin is contraindicated during pregnancy and in women who may become pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of warfarin therapy may outweigh the risks. If warfarin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Warfarin crosses the placenta, and fetal plasma concentrations are similar to maternal values. Warfarin embryopathy is especially prominent when taken during the first trimester after the 6th week of gestation, and may cause fetal hemorrhage and an increased risk of spontaneous abortion and fetal mortality. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system (CNS) and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy. In pregnant women with mechanical heart valves, adjusted-dose heparin or adjusted-dose LWWH (e.g., enoxaparin) may be used throughout pregnancy or until the 13th week of pregnancy when therapy may be changed to warfarin until close to delivery when adjusted-dose heparin or adjusted-dose LMWH should be resumed. In women at very high risk for thromboembolism (e.g., older generation prosthesis in the mitral position or history of thromboembolism) in whom the efficacy and safety of heparin or LMWH is of concern, warfarin may be used throughout pregnancy (in addition to low-dose aspirin) and replaced by heparin or LMWH close to delivery. Warfarin should not be used during labor or immediately after obstetric delivery because of the possibility of hemorrhage.

Children, infants, neonates

The safety and efficacy of warfarin have not been established in neonates, infants, children, or adolescents in randomized, controlled clinical trials. However, the use of warfarin in pediatric patients is well-documented for the prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic PT/INR ranges in the pediatric patient has been reported. The manufacturer recommends more frequent PT/INR determinations due to the possibility of changing warfarin requirements.

Breast-feeding

Warfarin was not present in human milk from mothers treated with warfarin from a limited published study. Human data are available; based on published data in 15 breast-feeding mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Effects in premature infants have not been evaluated. Because of the potential for serious adverse reactions, including bleeding in a breast-fed infant, consider the developmental and health benefits of breast-feeding along with the mother's clinical need for warfarin and any potential adverse effects on the breast-fed infant from warfarin or the underlying maternal condition. Previous American Academy of Pediatrics considered warfarin as usually compatible with breast-feeding. Monitor breast-feeding infants for bleeding or bruising.

Contraception requirements, pregnancy testing, reproductive risk

Counsel patients about reproductive risk and contraception requirements during warfarin treatment. Warfarin can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential are advised to use effective contraception during treatment and for at least 1 month after the final dose of warfarin. Verify the pregnancy status of females of reproductive potential with pregnancy testing prior to initiating warfarin therapy. Patients who are planning pregnancy and are receiving warfarin should be counseled regarding the risks of warfarin therapy before pregnancy occurs. If pregnancy is still desired, patients should be advised to either replace warfarin with LMWH (e.g., enoxaparin) or heparin before conception is attempted or undergo frequent pregnancy tests and substitute LWMH or heparin for warfarin as soon as pregnancy occurs.

DRUG INTERACTIONS

Abciximab: The use of abciximab within 7 days of use an oral anticoagulant is contraindicated unless the patient's prothrombin time is less than or equal to 1.2 times the control value. Because abciximab inhibits platelet aggregation, additive effects may be seen when abciximab is given in combination with other agents that affect hemostasis such as other platelet inhibitors (e.g. aspirin, ASA, clopidogrel, dipyridamole, ticlopidine), thrombolytic agents (e.g. alteplase, reteplase, streptokinase), and anticoagulants (e.g., heparin, warfarin). However, in clinical trials with abciximab, aspirin and heparin were administered concomitantly. The bleeding risk is significantly increased with concurrent abciximab and thrombolytic therapy; the risks of combination therapy should be weighed against the potential benefits. The GUSTO V study evaluated reduced-dose reteplase in combination with full dose abciximab, in comparison to full dose reteplase alone in patients with acute myocardial infarction (MI); all patients received concurrent aspirin and heparin therapy. The combination regimen was associated with a two-fold increase in moderate to severe non-intracranial bleeding complications, including spontaneous GI bleeding. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Although NSAIDs lacks platelet inhibitory effects, an increased risk for GI bleeding is possible when NSAIDs are administered during abciximab therapy. Acarbose: One case report of an interaction between warfarin and acarbose has been published. The addition of acarbose at a dosage of 25 mg three times per day resulted in an increased INR of 4.85 within two weeks. INRs should be closely observed during the first month of acarbose or miglitol therapy. Acebutolol: Per the prescribing information for warfarin sodium, concomitant use of beta-blockers and warfarin may result in elevations in PT/INR response. As propranolol has been shown to increase warfarin AUC and concurrent increases in INR values have been reported, patients receiving warfarin should be monitored for changes in the INR when beta-blockers are initiated or discontinued, or if the dosage is changed. Acetaminophen: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Aspirin, ASA; Caffeine: Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Butalbital: A serious drug interaction can occur between barbiturates and warfarin. All barbiturates are hepatic enzyme inducers and the clinical effects of warfarin can be compromised if a barbiturate is added. More importantly, discontinuation of a barbiturate during warfarin therapy has lead to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Butalbital; Caffeine: A serious drug interaction can occur between barbiturates and warfarin. All barbiturates are hepatic enzyme inducers and the clinical effects of warfarin can be compromised if a barbiturate is added. More importantly, discontinuation of a barbiturate during warfarin therapy has lead to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Butalbital; Caffeine; Codeine: A serious drug interaction can occur between barbiturates and warfarin. All barbiturates are hepatic enzyme inducers and the clinical effects of warfarin can be compromised if a barbiturate is added. More importantly, discontinuation of a barbiturate during warfarin therapy has lead to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Caffeine; Dihydrocodeine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: Coadministration of salicylates and warfarin may result in an increased risk of bleeding. Salicylates may displace warfarin from protein binding sites leading to increased anticoagulation effects. Hypoprothrombinemia, an additional risk factor for bleeding, also has been reported with salicylates. Non-acetylated salicylates do not appear to affect platelet aggregation in the same manner as aspirin and are associated with a lower risk of bleeding when given currently with warfarin. If salicylates and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Codeine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Dextromethorphan: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Dextromethorphan; Doxylamine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Dextromethorphan; Phenylephrine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Dextromethorphan; Pseudoephedrine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Dichloralphenazone; Isometheptene: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Diphenhydramine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Guaifenesin; Phenylephrine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Hydrocodone: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Oxycodone: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Pentazocine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Propoxyphene: Agents that inhibit cytochrome P450 CYP isoenzymes, such as propoxyphene, may decrease the metabolism of warfarin leading to increased anticoagulation effects. Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Pseudoephedrine: Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetaminophen; Tramadol: Elevation of prothrombin times during concurrent tramadol and warfarin usage has been reported rarely during the post-marketing period. Increased INRs have been reported in patients previously stabilized on warfarin who start taking tramadol. For example, a patient stabilized on warfarin 5 mg/daily had an increased INR from 3.5 to 7.1. He had begun tramadol 50 mg three times daily 1 month earlier. In another case, addition of tramadol 50 mg every 6 hours to a stable dose of warfarin 45 mg/week resulted in an INR of 10.6. The patient had begun tramadol about 2 weeks before presentation and stopped tramadol 2-3 days earlier. Cessation of warfarin and slow reinstitution of 45 mg/week led to a therapeutic INR. The mechanism of the interaction is unknown; tramadol is not highly protein bound and is not known to affect enzymes associated with the metabolism of warfarin. Closely monitor patients who require the combination of tramadol and warfarin for changes in INR and bleeding. Another alternative analgesic agent may be warranted in patients receiving warfarin. Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days. Acetazolamide: Per the prescribing information for warfarin sodium, concomitant use of carbonic anhydrase inhibitors (or other diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Ado-Trastuzumab emtansine: Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors. Albendazole: Albendazole induces cytochrome P450 1A (CYP1A) and although not studied, may induce the metabolism of R-warfarin. Patients receiving albendazole in combination should be closely monitored when albendazole is prescribed. Conversely, the discontinuation of albendazole therapy may result in a reduced clearance of R-warfarin, leading to an increase in anticoagulant effect. The patient's clinical status and INR should be monitored carefully when albendazole is prescribed and on discontinuation of albendazole therapy. Aliskiren: Coadministration of warfarin with aliskrien decreases the absorption (Cmax) of warfarin by up to 12%. During clinical evaluation, coadministration did not reveal any significant effect on blood coagulation parameters in tested blood samples. Nevertheless, blood coagulation markers should be closely monitored in patients taking both of these medications. Aliskiren; Amlodipine: Coadministration of warfarin with aliskrien decreases the absorption (Cmax) of warfarin by up to 12%. During clinical evaluation, coadministration did not reveal any significant effect on blood coagulation parameters in tested blood samples. Nevertheless, blood coagulation markers should be closely monitored in patients taking both of these medications. Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: Coadministration of warfarin with aliskrien decreases the absorption (Cmax) of warfarin by up to 12%. During clinical evaluation, coadministration did not reveal any significant effect on blood coagulation parameters in tested blood samples. Nevertheless, blood coagulation markers should be closely monitored in patients taking both of these medications. Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Aliskiren; Hydrochlorothiazide, HCTZ: Coadministration of warfarin with aliskrien decreases the absorption (Cmax) of warfarin by up to 12%. During clinical evaluation, coadministration did not reveal any significant effect on blood coagulation parameters in tested blood samples. Nevertheless, blood coagulation markers should be closely monitored in patients taking both of these medications. Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Aliskiren; Valsartan: Coadministration of warfarin with aliskrien decreases the absorption (Cmax) of warfarin by up to 12%. During clinical evaluation, coadministration did not reveal any significant effect on blood coagulation parameters in tested blood samples. Nevertheless, blood coagulation markers should be closely monitored in patients taking both of these medications. Allopurinol: Allopurinol may interfere with the metabolism of warfarin. The INR should be monitored carefully in patients receiving oral anticoagulants when allopurinol therapy is added. Alteplase, tPA: Based on the pharmacology of warfarin, other thrombolytic agents could cause additive risk of bleeding when given concurrently with warfarin. Pre-treatment with oral anticoagulants is reported to be an independent risk factor for intracranial hemorrhage in thrombolytic-treated patients. Prothrombin times stabilized during administration of both agents will change slightly when heparin is discontinued. Altretamine: Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Amikacin: The concomitant use of warfarin with many classes of antibiotics, including aminoglycosides, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Amiloride: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Amiloride; Hydrochlorothiazide, HCTZ: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Amiodarone: Amiodarone and its metabolites inhibit the metabolism of both R- and S-warfarin, but the metabolism of S-warfarin is more strongly inhibited. Concurrent administration of amiodarone with coumarin or indandione anticoagulants (warfarin), results in at least a doubling of prothrombin time, significantly increasing the INR in virtually all patients receiving this drug combination and can cause serious or potentially fatal hemorrhagic complications. This effect can occur as early as 4-6 days following the initial administration of the drugs in combination but can be delayed for weeks in some cases. Given the extremely long half-life of amiodarone, the interaction may persist for weeks or even months after discontinuance of amiodarone. In general, a range between 20 to 50% reduction in warfarin dosage has been recommended when amiodarone therapy is initiated. The manufacturer recommends 33-50% reduction in warfarin dosage when amiodarone therapy is initiated. Intensive clinical observation and frequent determination of PT and INR values is warranted to evaluate the extent of the interaction and guide further adjustments in therapy. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, closely monitor INR. Amitriptyline; Chlordiazepoxide: Chlordiazepoxide has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed. Amlodipine; Atorvastatin: Per the manufacturer of atorvastatin, a clinically significant effect on the prothrombin time when atorvastatin is administered to patients receiving chronic warfarin therapy has not been documented. In a study by the manufacturer, patients chronically maintained on warfarin were administered atorvastatin (80 mg/day) for 2 weeks. Mean prothrombin times decreased slightly, but only for the first few days of treatment. Per prescribing information for warfarin sodium (Coumadin), however, all HMG-CoA reductase inhibitors (statins), including atorvastatin, have been associated with potentiation of warfarin's clinical effect. In patients taking atorvastatin, it may be prudent to monitor the INR at baseline, at initiation of atorvastatin, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions. Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Amlodipine; Telmisartan: The coadministration of telmisartan and warfarin may lead to a decrease in the anticoagulation effects of warfarin. Amobarbital: A serious drug interaction can occur between barbiturates and warfarin. All barbiturates are hepatic enzyme inducers and the clinical effects of warfarin can be compromised if a barbiturate is added. More importantly, discontinuation of a barbiturate during warfarin therapy has lead to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. Amoxicillin: The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Amoxicillin; Clarithromycin; Lansoprazole: Clarithromycin may potentiate warfarin effects by inhibiting its metabolism by hepatic isozyme CYP3A4. Unlike other macrolides, dirithromycin and azithromycin have less of an effect on cytochrome P450 isoenzymes and drug interaction studies have not shown a significant interaction with dairithromycin and warfarin. However, there have been post-market case reports of increased INR with the combination. This interaction may be severe in critically ill patients. Close monitoring of the prothrombin time and INR is recommended in patients receiving macrolides with warfarin. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Amoxicillin; Clarithromycin; Omeprazole: Clarithromycin may potentiate warfarin effects by inhibiting its metabolism by hepatic isozyme CYP3A4. Unlike other macrolides, dirithromycin and azithromycin have less of an effect on cytochrome P450 isoenzymes and drug interaction studies have not shown a significant interaction with dairithromycin and warfarin. However, there have been post-market case reports of increased INR with the combination. This interaction may be severe in critically ill patients. Close monitoring of the prothrombin time and INR is recommended in patients receiving macrolides with warfarin. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Amoxicillin; Clavulanic Acid: The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Ampicillin: The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Ampicillin; Sulbactam: The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Amprenavir: Many antiretroviral agents may interact with warfarin. Agents that inhibit cytochrome P450 (CYP) isoenzymes 3A4, 1A2, or 2C9 may decrease the metabolism of warfarin leading to increased anticoagulation effects. Interactions may occur when warfarin is given with anti-retroviral protease inhibitors. Ritonavir may have induction or inhibition affects on warfarin metabolism. When warfarin (single dose of 5 mg) is administered with ritonavir (400 mg every 12 hours) a 9% increase in warfarin AUC and a 9% decrease in warfarin Cmax is seen. The high vitamin E content in amprenavir formulations may exacerbate the effects of warfarin. Patients should be carefully monitored for changes in INR, with the potential need for warfarin dosage adjustments, if warfarin and antiretroviral agents are coadministered. Anagrelide: Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other platelet inhibitors (e.g. aspirin, ASA, cilostazol, clopidogrel, ticlopidine), thrombolytic agents (e.g. alteplase, reteplase, streptokinase), anticoagulants (e.g., heparin, warfarin), or NSAIDs. Warfarin is a substrate of CYP1A2; anagrelide has been shown to inhibit CYP1A2. Monitor patients for increased therapeutic effect of warfarin, including an increase in the INR, if these drugs are coadministered. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin. Anthracyclines: Due to the thrombocytopenic effects of anthracyclines, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, rivaroxaban is a mild P-glycoprotein (P-gp) inhibitor and doxorubicin is a major substrate of P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of rivaroxaban and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. Antithrombin III: As a regulator of hemostasis, antithrombin III (AT III) may increase bleeding risk in patients receiving warfarin concomitantly. The half-life of AT III may be altered during concomitant administration with anticoagulants. Patients should be monitored for appropriate anticoagulation during coadministration of AT III and coumarin anticoagulants. Antithymocyte Globulin: Drugs that can cause thrombocytopenia, such as antithymocyte globulin, may lead to an increased risk of bleeding when given concurrently with anticoagulants. Apixaban: Due to the increased bleeding risk, avoid concurrent use of apixaban with warfarin. If switching from warfarin to apixaban, discontinue warfarin and administer apixaban when the INR is < 2. If switching from apixaban to warfarin, discontinue apixaban and begin both a parenteral anticoagulant and warfarin at the time the next apixaban dose would have been taken. Discontinue the parenteral anticoagulant when the INR is therapeutic. Monitor the patient closely for signs of bleeding. Aprepitant, Fosaprepitant: Coadministration of warfarin with aprepitant, fosaprepitant may result in a clinically significant decrease in warfarin serum concentrations and in the International Normalized Ratio (INR). Aprepitant, fosaprepitant is an inducer of isoenzyme CYP2C9, an enzyme involved in warfarin metabolism. In patients receiving chronic warfarin, the INR should be closely monitored during the 2 week period (particularly at 7-10 days) after the initiation of aprepitant, fosaprepitant dosage regimen (3 days) with each chemotherapy cycle. Studies have noted a 34% decrease in S-warfarin trough concentrations, accompanied by a 14% decrease in the INR at five days after completion of the aprepitant, fosaprepitant regimen. Argatroban: An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., heparin, warfarin) in combination with argatroban. Armodafinil: Interaction studies between armodafinil and warfarin have not been conducted. A single dose study of warfarin and modafinil, a racemic compound containing armodafinil, did not produce significant changes in the pharmacokinetic profile of warfarin. However, the manufacturer of armodafinil suggests consideration of more frequent monitoring of prothrombin times and INR values when armodafinil and warfarin are coadministered. Arsenic Trioxide: An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly. Ascorbic Acid, Vitamin C: There are reports that high doses of ascorbic acid may decrease the anticoagulation effects of warfarin. No clinical intervention appears to be necessary unless large doses of ascorbic acid are being consumed. Aspirin, ASA: Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. Aspirin, ASA; Butalbital; Caffeine: A serious drug interaction can occur between barbiturates and warfarin. All barbiturates are hepatic enzyme inducers and the clinical effects of warfarin can be compromised if a barbiturate is added. More importantly, discontinuation of a barbiturate during warfarin therapy has lead to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. Aspirin, ASA; Butalbital; Caffeine; Codeine: A serious drug interaction can occur between barbiturates and warfarin. All barbiturates are hepatic enzyme inducers and the clinical effects of warfarin can be compromised if a barbiturate is added. More importantly, discontinuation of a barbiturate during warfarin therapy has lead to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. Aspirin, ASA; Caffeine; Dihydrocodeine: Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. Aspirin, ASA; Carisoprodol: Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. Aspirin, ASA; Carisoprodol; Codeine: Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. Aspirin, ASA; Dipyridamole: Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis. Per the manufacturer, dipyridamole does not influence prothrombin time or activity when administered with warfarin; bleeding frequency and severity are similar when dipyridamole is administered with or without warfarin. In rare cases, however, increased bleeding has been observed during or after surgery. Regardless, caution is advised as both anticoagulants including warfarin and platelet inhibitors such as dipyridamole affect hemostasis and combination therapy could increase the risk of bleeding. Aspirin, ASA; Omeprazole: Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. Aspirin, ASA; Oxycodone: Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. Aspirin, ASA; Pravastatin: Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. Coadministration of pravastatin (40 mg) has been reported to have no clinically significant effect on prothrombin time in normal elderly subjects previously stabilized on warfarin. However, per prescribing information for warfarin sodium (Coumadin), all HMG-CoA reductase inhibitors (statins), including pravastatin, have been associated with potentiation of warfarin's clinical effect. However, it appears that pravastatin may be less likely to significantly interact with warfarin based on drug interaction studies. In general, it is prudent to monitor INR at baseline, at initiation of pravastatin, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions. Atazanavir: Many antiretroviral agents may interact with warfarin. Agents that inhibit cytochrome P450 (CYP) isoenzymes 3A4, 1A2, or 2C9 may decrease the metabolism of warfarin leading to increased anticoagulation effects. Interactions may occur when warfarin is given with anti-retroviral protease inhibitors. Ritonavir may have induction or inhibition affects on warfarin metabolism. When warfarin (single dose of 5 mg) is administered with ritonavir (400 mg every 12 hours) a 9% increase in warfarin AUC and a 9% decrease in warfarin Cmax is seen. The high vitamin E content in amprenavir formulations may exacerbate the effects of warfarin. Patients should be carefully monitored for changes in INR, with the potential need for warfarin dosage adjustments, if warfarin and antiretroviral agents are coadministered. Atazanavir; Cobicistat: Many antiretroviral agents may interact with warfarin. Agents that inhibit cytochrome P450 (CYP) isoenzymes 3A4, 1A2, or 2C9 may decrease the metabolism of warfarin leading to increased anticoagulation effects. Interactions may occur when warfarin is given with anti-retroviral protease inhibitors. Ritonavir may have induction or inhibition affects on warfarin metabolism. When warfarin (single dose of 5 mg) is administered with ritonavir (400 mg every 12 hours) a 9% increase in warfarin AUC and a 9% decrease in warfarin Cmax is seen. The high vitamin E content in amprenavir formulations may exacerbate the effects of warfarin. Patients should be carefully monitored for changes in INR, with the potential need for warfarin dosage adjustments, if warfarin and antiretroviral agents are coadministered. Close monitoring of the international normalized ration (INR) is advised when administering warfarin concurrently with cobicistat. Serum concentrations of warfarin may be altered during coadministration. Cobicistat is an inhibitor of CYP3A4; an isoenzymes partially responsible for the metabolism of warfarin. These drugs used in combination may result in increased warfarin plasma concentrations. Atenolol: Atenolol has been associated with elevations in the INR in some patients when used in combination with warfarin. Atenolol does not appear to cause changes in warfarin elimination half-life, and studies suggest there is a slight alteration in warfarin AUC. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Atenolol; Chlorthalidone: Chlorthalidone has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed. Atenolol has been associated with elevations in the INR in some patients when used in combination with warfarin. Atenolol does not appear to cause changes in warfarin elimination half-life, and studies suggest there is a slight alteration in warfarin AUC. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Atorvastatin: Per the manufacturer of atorvastatin, a clinically significant effect on the prothrombin time when atorvastatin is administered to patients receiving chronic warfarin therapy has not been documented. In a study by the manufacturer, patients chronically maintained on warfarin were administered atorvastatin (80 mg/day) for 2 weeks. Mean prothrombin times decreased slightly, but only for the first few days of treatment. Per prescribing information for warfarin sodium (Coumadin), however, all HMG-CoA reductase inhibitors (statins), including atorvastatin, have been associated with potentiation of warfarin's clinical effect. In patients taking atorvastatin, it may be prudent to monitor the INR at baseline, at initiation of atorvastatin, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions. Atorvastatin; Ezetimibe: Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored. Per the manufacturer of atorvastatin, a clinically significant effect on the prothrombin time when atorvastatin is administered to patients receiving chronic warfarin therapy has not been documented. In a study by the manufacturer, patients chronically maintained on warfarin were administered atorvastatin (80 mg/day) for 2 weeks. Mean prothrombin times decreased slightly, but only for the first few days of treatment. Per prescribing information for warfarin sodium (Coumadin), however, all HMG-CoA reductase inhibitors (statins), including atorvastatin, have been associated with potentiation of warfarin's clinical effect. In patients taking atorvastatin, it may be prudent to monitor the INR at baseline, at initiation of atorvastatin, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions. Atovaquone; Proguanil: The anticoagulant effects of warfarin and other coumarin-based anticoagulants may be increased when used concomitantly with proguanil; the mechanism of the interaction is not known. If proguanil is initiated in someone receiving warfarin, monitor the patient closely for an increased INR or symptoms of bleeding. Atropine; Hyoscyamine; Phenobarbital; Scopolamine: A serious drug interaction can occur between barbiturates and warfarin. All barbiturates are hepatic enzyme inducers and the clinical effects of warfarin can be compromised if a barbiturate is added. More importantly, discontinuation of a barbiturate during warfarin therapy has lead to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. Azathioprine: Azathioprine decreases warfarin serum concentrations and the INR and thus increases warfarin dosage requirements. If azathioprine is discontinued in a patient stabilized on warfarin, an increased risk of bleeding may occur. It is prudent to monitor the INR and response to warfarin prior to azathioprine initiation, frequently following initiation of azathioprine therapy, and again on azathioprine cessation. Adjust warfarin dosage based on INR and clinical response. Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: L-methylfolate and warfarin should be used together cautiously. Significant impairment of folate status may occur after 6 months of therapy with warfarin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together. Niacin (nicotinic acid) is occasionally associated with small but statistically significant increases (mean 4%) in prothrombin time. While rare, there is a possibility that an interaction would occur in some patients stabilized on warfarin. It appears prudent to monitor the INR periodically. Azilsartan; Chlorthalidone: Chlorthalidone has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed. Azithromycin: Azithromycin did not affect the prothrombin time response to a single dose of warfarin. Compared to other macrolides, azithromycin has less of an effect on cytochrome P450 isoenzymes. Reports of an interaction between azithromycin and warfarin have been made to the manufacturers suggesting that concomitant admininstration may potentiate the effects of warfarin. Monitor the INR in patients who receive warfarin and azithromycin concurrently as a potential interaction may occur. The concurrent use of other macrolides and warfarin in medical practice has been associated with increased anticoagulant effects. Aztreonam: The concomitant use of warfarin with many classes of antibiotics, including aztreonam, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Balsalazide: Increased prothrombin time in patients taking concomitant 5-aminosalicylates and warfarin has been reported. Closely monitor patients PT and INR during and following concomitant balsalazide therapy; dosage adjustments of anticoagulants may be necessary. Barbiturates: A serious drug interaction can occur between barbiturates and warfarin. All barbiturates are hepatic enzyme inducers and the clinical effects of warfarin can be compromised if a barbiturate is added. More importantly, discontinuation of a barbiturate during warfarin therapy has lead to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. Belladonna Alkaloids; Ergotamine; Phenobarbital: A serious drug interaction can occur between barbiturates and warfarin. All barbiturates are hepatic enzyme inducers and the clinical effects of warfarin can be compromised if a barbiturate is added. More importantly, discontinuation of a barbiturate during warfarin therapy has lead to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. Benazepril; Hydrochlorothiazide, HCTZ: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Bendroflumethiazide; Nadolol: Per the prescribing information for warfarin sodium, concomitant use of beta-blockers and warfarin may result in elevations in PT/INR response. As propranolol has been shown to increase warfarin AUC and concurrent increases in INR values have been reported, patients receiving warfarin should be monitored for changes in the INR when beta-blockers are initiated or discontinued, or if the dosage is changed. Betaxolol: Per the prescribing information for warfarin sodium, concomitant use of beta-blockers and warfarin may result in elevations in PT/INR response. As propranolol has been shown to increase warfarin AUC and concurrent increases in INR values have been reported, patients receiving warfarin should be monitored for changes in the INR when beta-blockers are initiated or discontinued, or if the dosage is changed. Bevacizumab: An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly. Bicalutamide: Bicalutamide has been shown in vitro to displace coumarin anticoagulants such as warfarin from protein-binding sites. Prothrombin times should be closely monitored in patients receiving warfarin and subsequently started on bicalutamide. Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: Metronidazole can potentiate the anticoagulant effect of warfarin. While the exact mechanism of metronidazole's effect on warfarin is unknown, there is a stereospecific increase of S-warfarin in humans. Data in rats suggest that the effects on S-warfarin may actually be due to stereoselective disruption of S-warfarin's protein binding by metronidazole, thereby increasing the active concentrations of S-warfarin. A study in humans examined S-warfarin and tolbutamide as probes for the CYP2C9 isoenzyme. Metronidazole interacted with S-warfarin, but not tolbutamide. This lessens the likelihood of a potential CYP2C9 interaction, which was originally postulated. Also, some antibiotics are known to destroy intestinal flora that synthesize vitamin K, and a decrease in the activity level of vitamin K can enhance warfarin's anticoagulant effect. Thus, the hypoprothrombinemic effects of warfarin can be potentiated if metronidazole is added. Prothrombin times should be monitored closely if metronidazole is added to warfarin therapy. Adjustment of the anticoagulant dosage may be necessary. Bismuth Subsalicylate: Coadministration of salicylates and warfarin may result in an increased risk of bleeding. Salicylates may displace warfarin from protein binding sites leading to increased anticoagulation effects. Hypoprothrombinemia, an additional risk factor for bleeding, also has been reported with salicylates. Non-acetylated salicylates do not appear to affect platelet aggregation in the same manner as aspirin and are associated with a lower risk of bleeding when given currently with warfarin. If salicylates and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Bismuth Subsalicylate; Metronidazole; Tetracycline: Metronidazole can potentiate the anticoagulant effect of warfarin. While the exact mechanism of metronidazole's effect on warfarin is unknown, there is a stereospecific increase of S-warfarin in humans. Data in rats suggest that the effects on S-warfarin may actually be due to stereoselective disruption of S-warfarin's protein binding by metronidazole, thereby increasing the active concentrations of S-warfarin. A study in humans examined S-warfarin and tolbutamide as probes for the CYP2C9 isoenzyme. Metronidazole interacted with S-warfarin, but not tolbutamide. This lessens the likelihood of a potential CYP2C9 interaction, which was originally postulated. Also, some antibiotics are known to destroy intestinal flora that synthesize vitamin K, and a decrease in the activity level of vitamin K can enhance warfarin's anticoagulant effect. Thus, the hypoprothrombinemic effects of warfarin can be potentiated if metronidazole is added. Prothrombin times should be monitored closely if metronidazole is added to warfarin therapy. Adjustment of the anticoagulant dosage may be necessary. Coadministration of salicylates and warfarin may result in an increased risk of bleeding. Salicylates may displace warfarin from protein binding sites leading to increased anticoagulation effects. Hypoprothrombinemia, an additional risk factor for bleeding, also has been reported with salicylates. Non-acetylated salicylates do not appear to affect platelet aggregation in the same manner as aspirin and are associated with a lower risk of bleeding when given currently with warfarin. If salicylates and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Bisoprolol: Per the prescribing information for warfarin sodium, concomitant use of beta-blockers and warfarin may result in elevations in PT/INR response. As propranolol has been shown to increase warfarin AUC and concurrent increases in INR values have been reported, patients receiving warfarin should be monitored for changes in the INR when beta-blockers are initiated or discontinued, or if the dosage is changed. Bisoprolol; Hydrochlorothiazide, HCTZ: Per the prescribing information for warfarin sodium, concomitant use of beta-blockers and warfarin may result in elevations in PT/INR response. As propranolol has been shown to increase warfarin AUC and concurrent increases in INR values have been reported, patients receiving warfarin should be monitored for changes in the INR when beta-blockers are initiated or discontinued, or if the dosage is changed. Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Bivalirudin: Based on the pharmacology of warfarin, other anticoagulants cause additive risk of bleeding when given concurrently with warfarin. Bivalirudin affects the International Normalized Ratio (INR). INR measurements made in patients being treated with bivalirudin may not be useful for determining the appropriate warfarin dose. Blinatumomab: No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as warfarin. The dose of the concomitant drug may need to be adjusted. Boceprevir: Monitoring of the international normalized ratio (INR) is advised when administering warfarin with boceprevir due to an increased potential for warfarin-related adverse events, such as bleeding or thrombosis. If warfarin dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Predictions about the interaction can be made based on the metabolic pathway of warfarin. Warfarin is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in altered warfarin plasma concentrations. Bosentan: Bosentan decreases the plasma concentrations of warfarin. Monitor INR closely when bosentan is initiated or discontinued in patients who are stabilized on warfarin therapy. Brimonidine; Timolol: Per the prescribing information for warfarin sodium, concomitant use of beta-blockers and warfarin may result in elevations in PT/INR response. As propranolol has been shown to increase warfarin AUC and concurrent increases in INR values have been reported, patients receiving warfarin should be monitored for changes in the INR when beta-blockers are initiated or discontinued, or if the dosage is changed. Bumetanide: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Bupropion: Bupropion may alter PT and/or INR. It may be prudent to monitor the INR when bupropion is added to an existing warfarin regimen. Downward dosage adjustments of warfarin and more frequent monitoring of the INR may be required during smoking cessation. Bupropion; Naltrexone: Bupropion may alter PT and/or INR. It may be prudent to monitor the INR when bupropion is added to an existing warfarin regimen. Downward dosage adjustments of warfarin and more frequent monitoring of the INR may be required during smoking cessation. Give the extended-release injectable suspension of naltrexone cautiously to patients taking anticoagulants. Steps should be taken to avoid the risk of bleeding and hematoma formation following intramuscular injection. Butabarbital: A serious drug interaction can occur between barbiturates and warfarin. All barbiturates are hepatic enzyme inducers and the clinical effects of warfarin can be compromised if a barbiturate is added. More importantly, discontinuation of a barbiturate during warfarin therapy has lead to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. Canakinumab: The formation of CYP450 enzymes is suppressed by increased concentrations of cytokines (e.g., IL-1) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during canakinumab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as warfarin. If canakinumab is initiated in a patient taking warfarin, check the INR; warfarin dose adjustment may be needed. Candesartan; Hydrochlorothiazide, HCTZ: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Capecitabine: Use caution and frequently monitor the PT/INR of patients receiving concomitant therapy with capecitabine and warfarin; adjust the dose of warfarin as appropriate. The manufacturer of capecitabine includes a black box warning for this interaction. Capecitabine and/or its metabolites are CYP2C9 inhibitors; S-warfarin is a CYP2C9 substrate. In a drug interaction study (n = 4), the mean AUC of S-warfarin (20 mg, single dose) was increased by 57% after administration with capecitabine (1,250 mg/m2 twice daily), and the clearance decreased by 37%; baseline corrected AUC of INR increased by 2.8-fold, and the maximum observed INR value increased by 91%. In a clinical pharmacology trial, altered coagulation parameters and/or bleeding, including death, were reported in patients taking capecitabine with either warfarin or another coumarin-derivative anticoagulant, phenprocoumon. Postmarketing reports have also shown clinically significant increases in the PT/INR within several days to months of initiating capecitabine therapy; in a few cases, these events occurred within 1 month of stopping capecitabine therapy. Alterations in bleeding time occurred in patients with and without liver metastases. Captopril; Hydrochlorothiazide, HCTZ: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Carbamazepine: Carbamazepine may induce the metabolism of warfarin requiring the dosage of warfarin to be increased, even doubled, over several weeks after initiating carbamazepine therapy. If carbamazepine is discontinued, dosage reductions of warfarin may be necessary. Patients on oral anticoagulation should be monitored closely for changes in INR when carbamazepine is added or discontinued from a patient's drug therapy regimen. Carbenicillin: Some penicillins (e.g., carbenicillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin. Carbidopa; Levodopa; Entacapone: In an interaction study, entacapone did not significantly change the plasma levels of S-warfarin while the AUC for R-warfarin increased on average by 18% (90% CI, 11-26%), and the INR values increased on average by 13% (90% CI 6-19%). Nevertheless, cases of significantly increased INR in patients concomitantly using warfarin have been reported during the postmarketing period of entacapone. Therefore, monitoring of INR is recommended when entacapone treatment is initiated or when the dose is increased for patients receiving warfarin. Carbonic anhydrase inhibitors: Per the prescribing information for warfarin sodium, concomitant use of carbonic anhydrase inhibitors (or other diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Carteolol: Per the prescribing information for warfarin sodium, concomitant use of beta-blockers and warfarin may result in elevations in PT/INR response. As propranolol has been shown to increase warfarin AUC and concurrent increases in INR values have been reported, patients receiving warfarin should be monitored for changes in the INR when beta-blockers are initiated or discontinued, or if the dosage is changed. Carvedilol: Per the prescribing information for warfarin sodium, concomitant use of beta-blockers and warfarin may result in elevations in PT/INR response. As propranolol has been shown to increase warfarin AUC and concurrent increases in INR values have been reported, patients receiving warfarin should be monitored for changes in the INR when beta-blockers are initiated or discontinued, or if the dosage is changed. Cefaclor: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefadroxil: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefazolin: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefdinir: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefditoren: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefepime: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefixime: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefoperazone: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefotaxime: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefotetan: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefoxitin: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefpodoxime: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefprozil: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Ceftazidime: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Ceftazidime; Avibactam: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Ceftibuten: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Ceftizoxime: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Ceftriaxone: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cefuroxime: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Celecoxib: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Cephalexin: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cephalosporins: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cephalothin: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Cephradine: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Ceritinib: Avoid the use of ceritinib, a CYP2C9 inhibitor, with CYP2C9 substrates that have a narrow therapeutic index, such as warfarin, as warfarin exposure may be increased. If co-administration is unavoidable, closely monitor the patient's INR and consider a warfarin dose reduction as necessary; monitor for signs and symptoms of bleeding. Chenodiol: Due to its potential for hepatotoxicity, chenodiol may affect the pharmacodynamics of warfarin. Patients with hepatic impairment may require a lower dosage of warfarin due to decreased warfarin metabolism and decreased production of coagulation factors. Coadministration with chenodiol can cause prolongation of the prothrombin time and increase the risk of bleeding. Monitor patients on concomitant therapy carefully. If prolongation of prothrombin time is observed, the warfarin dosage should be adjusted as needed to produce a prothrombin time 1.5 to 2 times normal. If necessary, discontinue chenodiol therapy. Chloral Hydrate: Chloral hydrate may enhance the anticoagulation effects of warfarin. Trichloroacetic acid, a metabolite of chloral hydrate displaces warfarin from its binding sites. The effect on warfarin anticoagulation is usually small and transient. Chlorambucil: Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Chlordiazepoxide: Chlordiazepoxide has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed. Chlordiazepoxide; Clidinium: Chlordiazepoxide has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed. Chlorothiazide: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Chlorthalidone: Chlorthalidone has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed. Chlorthalidone; Clonidine: Chlorthalidone has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed. Cholestyramine: Cholestyramine can either increase or decrease the hypoprothrombinemic actions of warfarin. Cholestyramine can bind with vitamin K in the diet, impairing vitamin K absorption, which, in turn, may increase warfarin's hypoprothrombinemic effect. Conversely, cholestyramine can bind with warfarin directly and impair warfarin bioavailability. To prevent altering warfarin pharmacokinetics, doses of warfarin and cholestyramine should be staggered by at least 4 to 6 hours. Cholestyramine should be prescribed cautiously to any patient receiving warfarin since cholestyramine may enhance systemic warfarin clearance. Choline Salicylate; Magnesium Salicylate: Coadministration of salicylates and warfarin may result in an increased risk of bleeding. Salicylates may displace warfarin from protein binding sites leading to increased anticoagulation effects. Hypoprothrombinemia, an additional risk factor for bleeding, also has been reported with salicylates. Non-acetylated salicylates do not appear to affect platelet aggregation in the same manner as aspirin and are associated with a lower risk of bleeding when given currently with warfarin. If salicylates and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Chondroitin; Glucosamine: Case reports have reported a possible interaction between chondroitin; glucosamine and warfarin or other coumarin anticoagulants, resulting in an increase in INR and a need for warfarin dosage adjustment. In one case report, the patient was taking twice the recommended dosage of a popular chondroitin; glucosamine supplement (Cosamin DS). Controlled clinical trials of chondroitin; glucosamine for the treatment of osteoarthritis have not reported drug interactions with oral anticoagulants at typical dosages of up to 1500 mg glucosamine; 1200 mg chondroitin/day PO. However, drug interactions with these supplements have not been specifically studied. Until more is known regarding the potential for chondroitin or glucosamine to interact with warfarin, it may be prudent to closely monitor patients stabilized on warfarin if these dietary supplements are added to their therapy regimen. Increased effects from concomitant anticoagulant drugs such as increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants such as warfarin until data confirming the safety of MSM in patients taking these drugs are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving warfarin should be observed for increased bleeding. There are reports that high doses of ascorbic acid may decrease the anticoagulation effects of warfarin. No clinical intervention appears to be necessary unless large doses of ascorbic acid are being consumed. Cilostazol: The safety of cilostazol has not been established with concomitant administration of heparin, other anticoagulants, or thrombolytic agents. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. While both cilostazol and warfarin are metabolized by cytochrome P450 CYP3A4 and CYP2C19, administration of cilostazol with a single dose of warfarin (25 mg) in healthy volunteers did not affect warfarin metabolism or effect changes in pro-times, bleeding times, or platelet aggregation. However, the effect of concomitant multiple dosing of cilostazol and warfarin has not been evaluated. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently. Regularly monitor the INR and other clinical parameters during the chronic concomitant administration of warfarin and cilostazol. Although the risk of bleeding is increased when clopidogrel is used concomitantly with thrombolytic agents, it is common to see patients receive these drugs simultaneously. Cimetidine: Concurrent administration of cimetidine and warfarin has lead to increased INR values and moderate to severe bleeding in some patients. Cimetidine appears to stereoselectively inhibit the hepatic clearance of R-warfarin versus the more potent S-warfarin isomer. Cimetidine does not appear to alter the production of vitamin-K dependent clotting factors, and changes in INR resulting from the interaction may exhibit much inter-patient variability. According to a review of warfarin drug interactions, the occurrence of a cimetidine-warfarin interaction is considered to be highly probable. It is preferable to avoid this combination and to select alternative acid-suppressive therapy. Cisapride: Data indicate that administration of cisapride to patients receiving oral anticoagulants (e.g., warfarin) may cause a prolongation in the prothrombin time and increase the INR. When using cisapride with warfarin, monitor the coagulation time during the initiation and discontinuation of cisapride. Warfarin dose adjustment may be necessary. Citalopram: Caution is advised during concurrent use of warfarin with citalopram. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if citalopram is added to or removed from the regimen of a patient stabilized on warfarin. Coadministration does not significantly affect the pharmacokinetics of either citalopram or warfarin, but does result in a small increase in prothrombin time (PT) that has been reported as clinically unimportant. SSRIs like citalopram can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding; however, the absolute risk is not known. Clarithromycin: Clarithromycin may potentiate warfarin effects by inhibiting its metabolism by hepatic isozyme CYP3A4. Unlike other macrolides, dirithromycin and azithromycin have less of an effect on cytochrome P450 isoenzymes and drug interaction studies have not shown a significant interaction with dairithromycin and warfarin. However, there have been post-market case reports of increased INR with the combination. This interaction may be severe in critically ill patients. Close monitoring of the prothrombin time and INR is recommended in patients receiving macrolides with warfarin. Clofarabine: Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Clopidogrel: Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants. At high concentrations in vitro, clopidogrel inhibits CYP2C9, and warfarin is a CYP2C9 substrate. Thus, clopidogrel could increase warfarin plasma concentrations. Although the administration of clopidogrel 75 mg per day did not alter the pharmacokinetics of S-warfarin or the INR in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. Although there are no in vivo data with which to predict the magnitude or clinical significance of these potential interactions, caution should be used when warfarin is coadministered with clopidogrel. Clozapine: The protein binding of clozapine is 97%; highly protein-bound medications can displace clozapine from its binding sites, predominantly alpha-1-acid glycoprotein. Clozapine, in turn, can increase the serum concentrations of digoxin or warfarin. Closely observe patients on other highly protein-bound drugs for an increased incidence of adverse effects. Cobicistat: Close monitoring of the international normalized ration (INR) is advised when administering warfarin concurrently with cobicistat. Serum concentrations of warfarin may be altered during coadministration. Cobicistat is an inhibitor of CYP3A4; an isoenzymes partially responsible for the metabolism of warfarin. These drugs used in combination may result in increased warfarin plasma concentrations. Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: Close monitoring of the international normalized ration (INR) is advised when administering warfarin concurrently with cobicistat. Serum concentrations of warfarin may be altered during coadministration. Cobicistat is an inhibitor of CYP3A4; an isoenzymes partially responsible for the metabolism of warfarin. These drugs used in combination may result in increased warfarin plasma concentrations. Close monitoring of the international normalized ration (INR) is advised when administering warfarin concurrently with elvitegravir. Serum concentrations of warfarin may be altered during coadministration. Elvitegravir is an inducer of CYP2C9; an isoenzymes partially responsible for the metabolism of warfarin. These drugs used in combination may result in decreased warfarin plasma concentrations. Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: Close monitoring of the international normalized ration (INR) is advised when administering warfarin concurrently with cobicistat. Serum concentrations of warfarin may be altered during coadministration. Cobicistat is an inhibitor of CYP3A4; an isoenzymes partially responsible for the metabolism of warfarin. These drugs used in combination may result in increased warfarin plasma concentrations. Close monitoring of the international normalized ration (INR) is advised when administering warfarin concurrently with elvitegravir. Serum concentrations of warfarin may be altered during coadministration. Elvitegravir is an inducer of CYP2C9; an isoenzymes partially responsible for the metabolism of warfarin. These drugs used in combination may result in decreased warfarin plasma concentrations. Cod Liver Oil: Cod liver oil should be used only with caution and with frequent monitoring in patients on concurrent anticoagulants. In a limited number of patients, the hypoprothrombinemic response to warfarin was increased following large doses of vitamin A. Additionally, omega-3 fatty acids contained in cod liver oil may inhibit platelet aggregation. Theoretically, the risk of bleeding may be increased, but some studies that combined omega-3 fatty acids and anticoagulant agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3 to 6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant cod liver oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly. Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly. Co-Enzyme Q10, Ubiquinone: Co-enzyme Q10, ubiquinone is structurally similar to vitamin K; a decreased response to warfarin has been noted if this dietary supplement is taken. Avoid concurrent use when possible. If co-enzyme Q10 is taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints. Colesevelam: Cholestyramine can decrease warfarin absorption. Staggering the doses of cholestyramine and warfarin is recommended but this may not completely avoid a drug interaction. Cholestyramine has also been shown to enhance the clearance of IV warfarin. Thus, it is theoretically possible that cholestyramine may interfere with the actions of warfarin after warfarin has been absorbed. Colestipol may be an acceptable alternative to cholestyramine in patients receiving warfarin, although, both cholestyramine and colestipol can decrease vitamin K absorption from the gut, which may indirectly affect the clinical response to warfarin. Colesevelam may also decrease vitamin K absorption from the gut and interfere with the clinical effects of warfarin. Colestipol: Colestipol may affect the hypoprothrombinemic actions of warfarin. Colestipol can bind with vitamin K in the diet, impairing vitamin K absorption, which, in turn, may increase warfarin's hypoprothrombinemic effect. Conversely, colestipol can bind with warfarin directly and impair warfarin bioavailability, although the effects of colestipol on warfarin absorption are less pronounced than the ability of cholestyramine to bind with warfarin. To avoid altering warfarin pharmacokinetics, doses of warfarin and colestipol should be staggered by at least 4-6 hours. Colestipol should be prescribed cautiously to any patient receiving warfarin, although colestipol may be an acceptable alternative to cholestyramine in a patient receiving warfarin who also requires therapy with a bile acid sequestrant. Colistimethate, Colistin, Polymyxin E: The concomitant use of warfarin with many antibiotics, including polymyxins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Collagenase: Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. There are reports that high doses of ascorbic acid may decrease the anticoagulation effects of warfarin. No clinical intervention appears to be necessary unless large doses of ascorbic acid are being consumed. COMT inhibitors: In an interaction study, entacapone did not significantly change the plasma levels of S-warfarin while the AUC for R-warfarin increased on average by 18% (90% CI, 11-26%), and the INR values increased on average by 13% (90% CI 6-19%). Nevertheless, cases of significantly increased INR in patients concomitantly using warfarin have been reported during the postmarketing period of entacapone. Therefore, monitoring of INR is recommended when entacapone treatment is initiated or when the dose is increased for patients receiving warfarin. Conivaptan: Conivaptan is a potent CYP3A4 inhibitor, and may alter the pharacokinetics of warfarin. Monitor the INR response when conivaptan intravenous infusion is administered during warfarin therapy. Corticosteroids: The effect of corticosteroids on oral anticoagulants (e.g., warfarin) is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids; however, limited published data exist, and the mechanism of the interaction is not well described. High-dose corticosteroids appear to pose a greater risk for increased anticoagulant effect. In addition, corticosteroids have been associated with a risk of peptic ulcer and gastrointestinal bleeding. Thus corticosteroids should be used cautiously and with appropriate clinical monitoring in patients receiving oral anticoagulants; coagulation indices (e.g., INR, etc.) should be monitored to maintain the desired anticoagulant effect. During high-dose corticosteroid administration, daily laboratory monitoring may be desirable. Cranberry, Vaccinium macrocarpon Ait.: Interactions with warfarin and cranberry juice (cranberry, Vaccinium macrocarpon Ait.) have been reported; however, the evidence describing the potential for interaction has been controversial. A single dose of 8 ounces of cranberry juice was not found to affect CYP2C9, the enzyme responsible for the metabolism of S-warfarin. Drinking small amounts of cranberry juice daily or occasional intake of cranberry juice as part of a healthy diet is not thought to be harmful for most patients. However, case reports are published which suggest cranberry may have the potential to destabilize warfarin therapy in some patients. At least 12 case reports have been received by the British MHRA Committee on Safety of Medicines (CSM) regarding potential interactions with either cranberry juice or sauce. As is often typical with case reports of warfarin interactions, many of the patients in published reports in the literature had confounding variables (e.g., other drug therapy, other dietary changes, polymorphisms for CYP2C9 and vitamin K epoxide reductase [VKORC1]) that might account for the observed INR changes. In one published case report a patient stabilized on warfarin experienced a substantially increased INR after drinking approximately 1.5 quarts (1420 mL) of cranberry juice cocktail daily for 2 days. After a period of allowing the INR to return to normal, the interaction was confirmed on re-challenge with cranberry juice. During both of the elevated INR episodes, no other factors were identified that would have resulted in an elevated INR in the patient, such as drug, herbal, disease, or other food interactions and a causality assessment revealed the interaction to be highly probable. In a prospective study of patients stabilized on warfarin (n= 30) who were randomized to placebo or 8 ounces/day of cranberry juice for 2 weeks, no change was noted in the plasma concentration of warfarin nor in the INRs measured. It is not particularly clear if warfarin would interact with cranberry supplements (e.g., dried extracts). At least one small prospective study reported a modest pharmacodynamic effect on the INR in healthy subjects (n= 12) receiving such supplements following a single 25-mg dose of warfarin. No change in warfarin plasma concentration, protein binding, platelet aggregation, or the activity of clotting factors II, VII, or X was noted; however, the modest increased INR noted in 6 of 12 subjects during cranberry treatment was considered significant by the authors. The British CSM recommends that patients limit or avoid cranberry juice intake, including cranberry capsules and concentrates, if on warfarin therapy until further data are available. Use caution until more is known about this potential interaction. The INR should be monitored as per current standards of care. Patients should report any unusual bleeding or bruising. There are reports that high doses of ascorbic acid may decrease the anticoagulation effects of warfarin. No clinical intervention appears to be necessary unless large doses of ascorbic acid are being consumed. Cyclophosphamide: Use caution if cyclophosphamide is used concomitantly with warfarin, as both increased and decreased effects of warfarin have been reported when they are used together. Cyclosporine: Two reports are noted of a severe interaction between cyclosporine and warfarin. In the first case, a 65-year-old female had a decrease of her INR by about 40% after oral cyclosporine 300 mg twice daily initiation. She had been receiving 18.75 mg of warfarin weekly for venous thromboembolism. Her warfarin requirement increased to 27.5 mg/week. After the increase in warfarin dose, cyclosporine blood concentrations remained within the therapeutic range, and the INR values became stable with the same warfarin dose. When warfarin was discontinued, cyclosporine blood concentrations remained unchanged. In the second case, cyclosporine concentrations fell after warfarin therapy was begun, but the patient was also receiving phenobarbital. Until more information is available, patients should have their INR monitored closely during and after concomitant cyclosporine usage. Cytarabine, ARA-C: Due to the thrombocytopenic effects of pyrimidine analogs, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Dabigatran: Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran. Dabrafenib: Avoid the concomitant use of dabrafenib, a CYP3A4 (moderate), CYP2C9, and CYP2C19 inducer, and warfarin, a CYP3A4, CYP2C9, and CYP2C19 substrate, as warfarin levels may decrease. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor INR closely to ensure therapeutic anticoagulation. Dalfopristin; Quinupristin: The concomitant use of warfarin with many antibiotics, including dalfopristin; quinupristin, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Dalteparin: An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., heparin, warfarin) in combination with dalteparin. Danaparoid: An additive risk of bleeding may be seen in patients receiving warfarin in combination with danaparoid. Monitoring of anticoagulant therapy by prothrombin time and Thrombotest is unreliable within 5 hours after danaparoid administration. Danazol: Androgens are associated with potentiation of the hypoprothrombinemic effect of warfarin. These interactions have resulted in bleeding episodes in some patients receiving coumarin derivatives along with danazol, esthylestrenol, methyltestosterone, oxandrolone, oxymetholone, or stanozolol. A multidose study of oxandrolone in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80-85% dose reduction) was necessary to maintain a target INR of 1.5. When oxandrolone is prescribed to patients being treated with warfarin, doses of warfarin may need to be decreased significantly to maintain a desirable INR level and diminish the risk of potentially serious bleeding. A case report describes an increased INR in a woman receiving topical testosterone propionate ointment and anticoagulation with warfarin. In addition, danazol and stanozolol (androgen-related compounds), are associated with potentiation of the hypoprothrombinemic effect of warfarin. Danazol may inhibit warfarin metabolism and/or may potentiate the anticoagulant effects by affecting the coagulation system, and has been associated with reports of serious bleeding events. When androgen therapy is initiated in a patient already receiving warfarin, the patient should be closely monitored with frequent evaluation of the INR and clinical parameters; the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen or androgen-related (danazol, stanozolol) therapy is changed or discontinued. Daptomycin: Since their is limited data reguarding the interaction of daptomycin and warfarin, the manufacturer recommends that anticoagulant activity be monitored for the first few days in patients receiving daptomycin and warfarin. Darunavir: Many antiretroviral agents may interact with warfarin. Agents that inhibit cytochrome P450 (CYP) isoenzymes 3A4, 1A2, or 2C9 may decrease the metabolism of warfarin leading to increased anticoagulation effects. Interactions may occur when warfarin is given with anti-retroviral protease inhibitors. Ritonavir may have induction or inhibition affects on warfarin metabolism. When warfarin (single dose of 5 mg) is administered with ritonavir (400 mg every 12 hours) a 9% increase in warfarin AUC and a 9% decrease in warfarin Cmax is seen. The high vitamin E content in amprenavir formulations may exacerbate the effects of warfarin. Patients should be carefully monitored for changes in INR, with the potential need for warfarin dosage adjustments, if warfarin and antiretroviral agents are coadministered. Darunavir; Cobicistat: Many antiretroviral agents may interact with warfarin. Agents that inhibit cytochrome P450 (CYP) isoenzymes 3A4, 1A2, or 2C9 may decrease the metabolism of warfarin leading to increased anticoagulation effects. Interactions may occur when warfarin is given with anti-retroviral protease inhibitors. Ritonavir may have induction or inhibition affects on warfarin metabolism. When warfarin (single dose of 5 mg) is administered with ritonavir (400 mg every 12 hours) a 9% increase in warfarin AUC and a 9% decrease in warfarin Cmax is seen. The high vitamin E content in amprenavir formulations may exacerbate the effects of warfarin. Patients should be carefully monitored for changes in INR, with the potential need for warfarin dosage adjustments, if warfarin and antiretroviral agents are coadministered. Close monitoring of the international normalized ration (INR) is advised when administering warfarin concurrently with cobicistat. Serum concentrations of warfarin may be altered during coadministration. Cobicistat is an inhibitor of CYP3A4; an isoenzymes partially responsible for the metabolism of warfarin. These drugs used in combination may result in increased warfarin plasma concentrations. Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Many antiretroviral agents may interact with warfarin. Agents that inhibit cytochrome P450 (CYP) isoenzymes 3A4, 1A2, or 2C9 may decrease the metabolism of warfarin leading to increased anticoagulation effects. Interactions may occur when warfarin is given with anti-retroviral protease inhibitors. Ritonavir may have induction or inhibition affects on warfarin metabolism. When warfarin (single dose of 5 mg) is administered with ritonavir (400 mg every 12 hours) a 9% increase in warfarin AUC and a 9% decrease in warfarin Cmax is seen. The high vitamin E content in amprenavir formulations may exacerbate the effects of warfarin. Patients should be carefully monitored for changes in INR, with the potential need for warfarin dosage adjustments, if warfarin and antiretroviral agents are coadministered. Dasatinib: Due to the thrombocytopenic and possible platelet inhibiting effects of dasatinib, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, dasatinib is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. Coadministration may result in increases in rivaroxaban exposure and may increase bleeding risk. Caution should be exercised if patients are required to take anticoagulants concomitantly with dasatinib. Decitabine: Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Deferasirox: Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants. Defibrotide: Coadministration of defibrotide with antithrombotic agents (anticoagulants and platelet inhibitors) and fibrinolytics (thrombolytic agents) is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotics (e.g.,heparin) and fibrinolytics (e.g., alteplase) are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic anticoagulant or fibrinolytic therapy (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the anticoagulant or fibrinolytic have abated. Delavirdine: Delavirdine inhibits CYP2C9 and may increase concentrations of warfarin, which is metabolized by this enzyme. Caution is recommended when administering delavirdine with warfarin. Denileukin Diftitox: An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. Desirudin: Any agent which may enhance the risk of hemorrhage should generally be discontinued before initiating desirudin therapy, including anticoagulants. If coadministration cannot be avoided, close clinical and laboratory monitoring should be conducted. The concomitant administration of warfarin did not significantly affect the pharmacokinetic effects of desirudin; however, greater inhibition of hemostasis measured by aPTT, PT, and INR was observed with coadministration. If a patient is switched from oral anticoagulants to desirudin therapy or from desirudin to oral anticoagulants, the anticoagulant activity should continue to be closely monitored with appropriate methods. That activity should be taken into account in the evaluation of the overall coagulation status of the patient during the switch. Desvenlafaxine: Platelet aggregation may be impaired by desvenlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner. Dexmethylphenidate: Although data are unavailable for dexmethylphenidate, racemic methylphenidate may decrease the metabolism of warfarin. Downward dosage adjustments of the anticoagulant may be required when dexmethylphenidate is used concomitantly. Close monitoring of the INR is recommended. Methylphenidate may decrease the metabolism of warfarin. Downward dosage adjustments of the anticoagulant may be required when methylphenidate is used concomitantly. Close monitoring of the INR is recommended. Dextran: Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently. Dextromethorphan; Quinidine: Quinidine may potentiate the anticoagulation effects of warfarin; bleeding has been reported. This interaction is probably due to additive hypoprothrombinemia associated with concomitant administration of warfarin and quinine or quinidine. Close monitoring of the INR is required when either of these agents is added to warfarin therapy. Diazoxide: Diazoxide can displace highly protein-bound drugs from their protein-binding sites, resulting in an increased therapeutic effect. This interaction should be considered when administering diazoxide concomitantly with other highly protein-bound drugs such as warfarin. Dichlorphenamide: Per the prescribing information for warfarin sodium, concomitant use of diuretics, including dichlorphenamide, and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Diclofenac: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Diclofenac; Misoprostol: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Dicloxacillin: The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Diflunisal: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Diphenhydramine; Ibuprofen: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Dipyridamole: Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis. Per the manufacturer, dipyridamole does not influence prothrombin time or activity when administered with warfarin; bleeding frequency and severity are similar when dipyridamole is administered with or without warfarin. In rare cases, however, increased bleeding has been observed during or after surgery. Regardless, caution is advised as both anticoagulants including warfarin and platelet inhibitors such as dipyridamole affect hemostasis and combination therapy could increase the risk of bleeding. Dirithromycin: Although drug interaction studies have not shown a significant interaction with dirithromycin and warfarin, there have been numerous reports of increased INR with the combination of warfarin with various macrolides (e.g., azithromycin, clarithromycin, erythromycin, troleandomycin); although, in some cases, causality has not been established. Close monitoring of the INR in patients who receive warfarin and dirithromycin is recommended until more data are available. Dirithromycin has less of an effect on cytochrome P450 isoenzymes than clarithromycin or erythromycin and significant interactions with warfarin are not expected in most patients. Disopyramide: A single case of the use of disopyramide with warfarin reported that discontinuation of disopyramide resulted in a drop in the prothrombin time; however, causality was not established and other factors may have contributed to reduction of anticoagulant effect. A direct interaction between disopyramide and warfarin has not been established. Disulfiram: Disulfiram can interfere with the metabolism of oral anticoagulants, increasing their serum concentrations and effects. In addition, disulfiram can act directly on the liver to enhance the hypoprothrombinemia precipitated by anticoagulant therapy. Prothrombin time should be performed prior to and during disulfiram administration and anticoagulant dosages adjusted accordingly. Doripenem: The concomitant use of warfarin with many classes of antibiotics, including carbapenems, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Dorzolamide; Timolol: Per the prescribing information for warfarin sodium, concomitant use of beta-blockers and warfarin may result in elevations in PT/INR response. As propranolol has been shown to increase warfarin AUC and concurrent increases in INR values have been reported, patients receiving warfarin should be monitored for changes in the INR when beta-blockers are initiated or discontinued, or if the dosage is changed. Dronabinol, THC: Use caution if coadministration of dronabinol with warfarin is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence) as well as increased bleeding or an increased PT/INR. Dronabinol is a CYP2C9 and 3A4 substrate; warfarin is a weak inhibitor of CYP2C9 in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol. Dronabinol is also highly bound to plasma proteins and may displace and increase the free fraction of other concomitantly administered protein-bound drugs such as warfarin. Dronedarone: Dronedarone is metabolized by CYP3A and is an inhibitor of CYP2D6. The CYP isoenzymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9 is the principle enzyme that metabolizes S-warfarin and modulates the in vivo activity of warfarin. CYP1A2 and CYP3A4 metabolize the R-isomer. In healthy subjects, dronedarone (600 mg BID) increased S-warfarin expsoure by 1.2-fold with no change in R-warfarin and no clinically significant increase in INR. In clinical trials involving patients with atrial fibrillation and/or atrial flutter, there was no excess risk of bleeding compared to placebo when dronedarone was coadministered with oral anticoagulants. Drospirenone; Ethinyl Estradiol; Levomefolate: L-methylfolate and warfarin should be used together cautiously. Significant impairment of folate status may occur after 6 months of therapy with warfarin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together. Drotrecogin Alfa: Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any anticoagulants. There is an additive risk of beeding. Duloxetine: Platelet aggregation may be impaired by duloxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner. Dutasteride; Tamsulosin: The manufacturer reports that results from limited in vitro and in vivo drug-drug interaction studies between tamsulosin and warfarin have been inconclusive; and therefore, tamsulosin should be used cautiously with warfarin. Echinacea: Warfarin is metabolized by both CYP1A2 and CYP3A4. In vivo data indicate that echinacea may inhibit hepatic CYP1A2, induce hepatic CYP3A4, and inhibit intestinal CYP3A4. The efficacy and safety of warfarin if used in combination with echinacea are unknown; however, close monitoring of patients for changes in efficacy or toxicity may be prudent if warfarin is used in combination with echinacea, until more data are available. Econazole: Coadministation of econazole and warfarin has resulted in enhanced anticoagulant effect. In many of these cases, absorption of econazole may have been increased by applying the drug under occlusion, to the genitals, or over large body surface areas. If these drugs are used in combination, closely monitor the International Normalized Ratio (INR) and/or prothrombin time. Edoxaban: Coadministration of edoxaban and other anticoagulants should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy. Efavirenz: Agents that inhibit CYP isoenzymes 3A4, 1A2, or 2C9, such as efavirenz, may decrease the metabolism of warfarin leading to increased anticoagulation effects. Monitor INR and adjust warfarin dosage as necessary. Efavirenz; Emtricitabine; Tenofovir: Agents that inhibit CYP isoenzymes 3A4, 1A2, or 2C9, such as efavirenz, may decrease the metabolism of warfarin leading to increased anticoagulation effects. Monitor INR and adjust warfarin dosage as necessary. Elbasvir; Grazoprevir: Administering warfarin with elbasvir; grazoprevir may result in elevated warfarin plasma concentrations. Warfarin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events. Eltrombopag: Use caution when discontinuing eltrombopag in patients receiving anticoagulants (e.g., warfarin, enoxaparin, dabigatran, rivaroxaban). The risk of bleeding and recurrent thrombocytopenia is increased in patients receiving these drugs when eltrombopag is discontinued. Elvitegravir: Close monitoring of the international normalized ration (INR) is advised when administering warfarin concurrently with elvitegravir. Serum concentrations of warfarin may be altered during coadministration. Elvitegravir is an inducer of CYP2C9; an isoenzymes partially responsible for the metabolism of warfarin. These drugs used in combination may result in decreased warfarin plasma concentrations. Enalapril; Hydrochlorothiazide, HCTZ: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Enflurane: All inhalational anesthetics, including enflurane, can increase the effects of warfarin, although the clinical significance of this interaction is not clear. Enoxaparin: An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding. Entacapone: In an interaction study, entacapone did not significantly change the plasma levels of S-warfarin while the AUC for R-warfarin increased on average by 18% (90% CI, 11-26%), and the INR values increased on average by 13% (90% CI 6-19%). Nevertheless, cases of significantly increased INR in patients concomitantly using warfarin have been reported during the postmarketing period of entacapone. Therefore, monitoring of INR is recommended when entacapone treatment is initiated or when the dose is increased for patients receiving warfarin. Enteral Feedings: Phytonadione, vitamin K1, is a pharmacologic antagonist of warfarin. Occult sources of vitamin K may decrease or reverse the activity of warfarin. Occult sources of vitamin K may include selected enteral feedings. In general, it is recommended that patients avoid large servings or frequent intake of foods that contain substantial amounts of vitamin K. Patients should aim for a stable and non-excessive intake of vitamin K in the diet to ensure stable INRs and appropriate clinical response to warfarin treatment. Enzalutamide: Avoid the concomitant use of enzalutamide, a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer, and warfarin, a CYP3A4, CYP2C9, and CYP2C19 substrate, as warfarin plasma exposure may be reduced. If coadministration of these agents is unavoidable, monitor INR frequently to ensure therapeutic anticoagulation. In a drug interaction trial in patients with castration-resistant prostate cancer, the AUC of warfarin was decreased following a single oral dose of warfarin 10 mg administered after at least 55 days of oral enzalutamide 160 mg/day; the Cmax value was minimally changed. Epoprostenol: When used concurrently with anticoagulants, epoprostenol may increase the risk of bleeding. Eprosartan; Hydrochlorothiazide, HCTZ: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Eptifibatide: Concomitant use of eptifibatide and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding. Erlotinib: International Normalized Ratio (INR) elevations and bleeding events including gastrointestinal and non-gastrointestinal bleeds (some cases fatal) have been reported with concomitant use of erlotinib and warfarin. Some reports of bleeding were associated with erlotinib and concomitant nonsteroidal antiinflammatory drugs (NSAIDs) usage. Patients taking warfarin or other coumarin-derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR. Ertapenem: The concomitant use of warfarin with many classes of antibiotics, including carbapenems, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Erythromycin: Erythromycin inhibits warfarin hepatic clearance, and concomitant use with warfarin can increase INR values. The INR should be monitored carefully if erythromycin is added to warfarin therapy. If warfarin is added after erythromycin therapy has begun, no special precautions appear to be necessary, however, if erythromycin is subsequently discontinued, warfarin dosages may need to be adjusted. Interactions between erythromycin and warfarin may be more pronounced in elderly patients. Erythromycin; Sulfisoxazole: Erythromycin inhibits warfarin hepatic clearance, and concomitant use with warfarin can increase INR values. The INR should be monitored carefully if erythromycin is added to warfarin therapy. If warfarin is added after erythromycin therapy has begun, no special precautions appear to be necessary, however, if erythromycin is subsequently discontinued, warfarin dosages may need to be adjusted. Interactions between erythromycin and warfarin may be more pronounced in elderly patients. Escitalopram: Caution is advised during concurrent use of warfarin with escitalopram. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if escitalopram is added to or removed from the regimen of a patient stabilized on warfarin. Coadministration did not significantly affect the pharmacokinetics of either citalopram (a racemic mixture containing escitalopram) or warfarin, but did result in a small increase in prothrombin time (PT) that was reported as clinically unimportant. SSRIs like escitalopram can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding; however, the absolute risk is not known. Eslicarbazepine: Coadministration of eslicarbazepine and warfarin may result in decreased efficacy of warfarin. Monitoring of INR during coadministration, particularly during eslicarbazepine titration and upon discontinuation of concomitant therapy, is recommened. Adjust the warfarin dose accordingly. Esmolol: Per the prescribing information for warfarin sodium, concomitant use of beta-blockers and warfarin may result in elevations in PT/INR response. As propranolol has been shown to increase warfarin AUC and concurrent increases in INR values have been reported, patients receiving warfarin should be monitored for changes in the INR when beta-blockers are initiated or discontinued, or if the dosage is changed. Esomeprazole; Naproxen: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Esterified Estrogens; Methyltestosterone: Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued. Estradiol; Levonorgestrel: Oral levonorgestrel-containing emergency contraceptive regimens may interact with warfarin and concurrent use may require patient education and monitoring. A case report of an interaction of warfarin with a levonorgestrel-only oral emergency contraceptive regimen has been described. The patient involved had familial antithrombin deficiency and was stabilized on warfarin as her only medication. The INR increased to 8.1 (without bleeding complications) from 2.1 within 3 days after receiving levonorgestrel. With corrective action, the warfarin was resumed at the usual dose without complication 2 days later. The report speculated that levonorgestrel displaced warfarin from plasma protein binding sites; however, inhibition of hepatic CYP2C9 by levonorgestrel may have decreased the metabolism of warfarin. This is the only report of this type of interaction available. Estramustine: An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. Estrogens: Because of contraindications to the use of oral contraceptives in patients with active thromboembolism risks, concurrent use of combined hormonal contraceptives is generally avoided in patients taking warfarin. However, per ACOG guidelines, in select patients the benefits of such contraception may outweigh the risks, as long as appropriate anticoagulant therapy is utilized. Alternative anticoagulants to warfarin may be considered. Oral contraceptives may inhibit CYP3A4 and CYP1A2, which can influence warfarin pharmacokinetics and also alter the INR; dosage adjustment of warfarin should be based on the prothrombin time or INR value. Isolated case reports have noted an augmented response to warfarin in patients receiving combined hormonal contraceptives. Estrogens increase the hepatic synthesis of prothrombin and factors VII, VIII, IX, and X and decrease antithrombin III; estrogens also increase norepinephrine-induced platelet aggregability. A positive relationship of estrogens to thromboembolic disease has been demonstrated, and the US FDA has suggested class labeling of estrogens for HRT, combined OCs and non-oral combination contraceptives in accordance with this data. OC products containing >= 50-mcg ethinyl estradiol are associated with the greatest risk of thromboembolic complications. The addition of certain progestins may also increase thromboembolic risks. Estrogens increase the hepatic synthesis of prothrombin and factors VII, VIII, IX, and X and decrease antithrombin III; estrogens also increase norepinephrine-induced platelet aggregability. A positive relationship between hormone replacement therapy and the risk of thromboembolic disease has been demonstrated in the Women's Health Initiative Trials (WHI trials). The US FDA has suggested class labeling of HRT products in accordance with this data. HRT products are generally contraindicated in patients with a current history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, thrombophlebitis (including pulmonary embolism and DVT), thromboembolic disease or valvular heart disease with complications. Concurrent use of HRT in female patients receiving anticoagulation therapy with warfarin is generally avoided. If concurrent use of an estrogen or estrogen-progestin containing HRT cannot be avoided in a patient taking warfarin, carefully monitor for signs and symptoms of thromboembolic complications. If such occur, the estrogen or estrogen-progestin containing HRT regimen should be discontinued. HRT is not expected to significantly alter the INR or to affect the metabolism of warfarin. Dosage adjustment of warfarin should be based on the prothrombin time or INR value. Ethacrynic Acid: Although data are very limited, there have been reports of increased hypoprothrombinemia when ethacrynic acid was administered to patients receiving warfarin. Per the prescribing information for warfarin sodium, concomitant use of diuretics and warfarin may result in an increased or decreased PT/INR. According to the manufacturer for ethacrynic acid, ethacrynic acid has been shown to displace warfarin from plasma protein; a reduction in the usual anticoagulant dosage may be required in patients receiving both drugs. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Ethanol: In controlled studies of patients or healthy subjects anticoagulated with warfarin, small to moderate amounts of wine (e.g., 2 drinks per day or less) do not alter INR values or warfarin levels. However, acute intoxication resulting from large amounts of ethanol may enhance the hypoprothrombinemic response to oral anticoagulants due to inhibition of warfarin's metabolism. Although chronic consumption of ethanol may increase warfarin clearance, studies have not demonstrated a reduction in anticoagulant effect. However, chronic consumption of alcohol may lead to hepatic disease, resulting in potentiation of hypoprothrombinemia due to impaired hepatic synthesis of clotting factors. In controlled studies of patients or healthy subjects anticoagulated with warfarin, small to moderate amounts of wine do not alter INR values or warfarin levels. However, acute intoxication resulting from large amounts of ethanol may enhance the hypoprothrombinemic response to oral anticoagulants due to inhibition of warfarin's metabolism. Ethinyl Estradiol; Levonorgestrel: Oral levonorgestrel-containing emergency contraceptive regimens may interact with warfarin and concurrent use may require patient education and monitoring. A case report of an interaction of warfarin with a levonorgestrel-only oral emergency contraceptive regimen has been described. The patient involved had familial antithrombin deficiency and was stabilized on warfarin as her only medication. The INR increased to 8.1 (without bleeding complications) from 2.1 within 3 days after receiving levonorgestrel. With corrective action, the warfarin was resumed at the usual dose without complication 2 days later. The report speculated that levonorgestrel displaced warfarin from plasma protein binding sites; however, inhibition of hepatic CYP2C9 by levonorgestrel may have decreased the metabolism of warfarin. This is the only report of this type of interaction available. Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: Oral levonorgestrel-containing emergency contraceptive regimens may interact with warfarin and concurrent use may require patient education and monitoring. A case report of an interaction of warfarin with a levonorgestrel-only oral emergency contraceptive regimen has been described. The patient involved had familial antithrombin deficiency and was stabilized on warfarin as her only medication. The INR increased to 8.1 (without bleeding complications) from 2.1 within 3 days after receiving levonorgestrel. With corrective action, the warfarin was resumed at the usual dose without complication 2 days later. The report speculated that levonorgestrel displaced warfarin from plasma protein binding sites; however, inhibition of hepatic CYP2C9 by levonorgestrel may have decreased the metabolism of warfarin. This is the only report of this type of interaction available. L-methylfolate and warfarin should be used together cautiously. Significant impairment of folate status may occur after 6 months of therapy with warfarin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together. Etidronate: There have been isolated reports of etidronate causing an increased prothrombin time/INR when the drug is given to patients stabilized on warfarin. Although none of the reports have described clinically significant sequelae, it is advisable to monitor the INR periodically in patients taking warfarin who have etidronate therapy added. Etodolac: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Etoposide, VP-16: Closely watch for bleeding and monitor the international normalized ratio (INR) of patients receiving concomitant treatment with etoposide, VP-16 and warfarin, as coadministration may result in an elevated INR. Etravirine: Coadministration with etravirine may lead to increased warfarin concentrations. If these drugs are coadministered, monitor the INR carefully and adjust the warfarin dose as needed. Exenatide: Cases of an increased INR have been reported with the concomitant use of warfarin and exenatide, sometimes associated with bleeding. Monitor for changes in INR and bleeding when these drugs are coadministered. Dosage adjustments of warfarin may be necessary. Ezetimibe: Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored. Ezetimibe; Simvastatin: Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored. Per prescribing information for warfarin sodium (Coumadin), all HMG-CoA reductase inhibitors (statins) have been associated with potentiation of warfarin's clinical effect. However, it appears that pravastatin and atorvastatin may be less likely to significantly interact with warfarin based on drug interaction studies. In addition, atorvastatin has been reported to slightly and transiently decrease the anticoagulant activity of warfarin; these effects were not considered clinically significant. In general, it is prudent to monitor INR at baseline, at initiation of these HMG Co-A reductase inhibitors, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions. Famotidine; Ibuprofen: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Fenofibrate: Fenofibrate potentiates the effects of warfarin and other oral anticoagulants, resulting in increased prothrombin times. Fibrates have been shown to decrease vitamin K dependent coagulation factor synthesis. Since these drugs are also highly protein-bound, it is possible that fenofibrate displaces warfarin from protein-binding sites as a potential mechanism. Case reports of significant effects on warfarin exist for all fibrate drugs. Three clinical case reports of fenofibrate and warfarin interactions have been reported in post-marketing surveillance of fenofibrate in the US and Europe. In one case, a 47 year old male who had been stable over a course of 20 weeks on his prescribed warfarin dose was admitted to the hospital one week after beginning treatment for hypertriglyceridemia with fenofibrate 201 mg/day. He presented with epigastric discomfort and hematuria. His INR on admission was > 8.5 (previously stabilized at 2 to 2.5 prior to fenofibrate). The patient received treatment with phytonadione and discontinuation of the medications. He was discharged 2 days later, but agreed to be rechallenged under a controlled protocol to confirm the interaction of the fenofibrate with his warfarin. After stabilization of his warfarin dose for 3 weeks, fenofibrate was restarted, and the patient was rechallenged on 2 occasions. Both times, an increase in INR above the therapeutic range occurred. Patients receiving warfarin in conjunction with fenofibrate should have frequent prothrombin time and INR determinations until it has been determined that the INR has been stabilized. A reduction in warfarin dose may be necessary. Fenofibric Acid: Fenofibric acid potentiates the effects of warfarin and other oral anticoagulants, resulting in increased prothrombin times. Fibrates have been shown to decrease vitamin K dependent coagulation factor synthesis. Since these drugs are also highly protein-bound, it is possible that fenofibric acid displaces warfarin from protein-binding sites as a potential mechanism. Case reports of significant effects on warfarin exist for all fibrate drugs. Fenofibric acid is the active metabolite of fenofibrate. Three clinical case reports of fenofibrate and warfarin interactions have been reported in post-marketing surveillance of fenofibrate in the US and Europe. In one case, a male (47 years) who had been stable over a course of 20 weeks on his prescribed warfarin dose was admitted to the hospital one week after beginning treatment for hypertriglyceridemia with fenofibrate 201 mg/day. He presented with epigastric discomfort and hematuria. His INR on admission was > 8.5 (previously stabilized at 2 to 2.5 prior to fenofibrate). The patient received treatment with phytonadione and discontinuation of the medications. He was discharged 2 days later, but agreed to be rechallenged under a controlled protocol to confirm the interaction of the fenofibrate with his warfarin. After stabilization of his warfarin dose for 3 weeks, fenofibrate was restarted, and the patient was rechallenged on 2 occasions. Both times, an increase in INR above the therapeutic range occurred. In order to prevent bleeding complications, patients receiving warfarin concomitantly with fenofibric acid should have frequent INR determinations until it has been determined that the INR has been stabilized. A reduction in warfarin dose may be necessary. Fenoprofen: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Ferric Citrate: According to the manufacturer of ferric citrate, it is not necessary to separate the timing of administration of ferric citrate from warfarin. However, because a reduction in the bioavailability of warfarin would have a clinically significant effect on its safety or efficacy, it may be prudent to monitor the clinical response to warfarin during concurrent use of ferric citrate. Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): Co-enzyme Q10, ubiquinone is structurally similar to vitamin K; a decreased response to warfarin has been noted if this dietary supplement is taken. Avoid concurrent use when possible. If co-enzyme Q10 is taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints. Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly. Flavocoxid, Flavocoxid; Citrated Zinc Bisglycinate: In vitro, flavocoxid, flavocoxid; citrated zinc bisglycinate demonstrated a 23% inhibition of CYP1A2 isoenzymes. This inhibition could potentially be clinically relevant, especially when flavocoxid, flavocoxid; citrated zinc bisglycinate is coadministered with CYP1A2 substrates that have a narrow therapeutic index such as warfarin. Until more data are available, it may be prudent to monitor for potential adverse effects of warfarin when coadministered with flavocoxid, flavocoxid; citrated zinc bisglycinate. Flaxseed: Flaxseed fiber can impair the absorption of oral drugs when administered concomitantly. However, no drug interaction studies have been performed to assess the degree to which the absorption of oral drugs may be altered. Based on interactions of other plant seed fiber (e.g., psyllium) used as a bulk-forming laxative, flaxseed fiber may adsorb oral anticoagulants (e.g., warfarin). Administration of prescribed oral agents should be separated from the administration of flaxseed fiber by at least 2 hours. Floxuridine: An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. Fluconazole: Fluconazole administered at low doses may affect warfarin hepatic metabolism only slightly while higher doses may significantly increase INR values. The INR should be monitored carefully in patients receiving warfarin if fluconazole is added. If warfarin is added after fluconazole therapy has begun, this interaction is of less significance. Fluorouracil, 5-FU: An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly. Fluoxetine: If possible, avoid concurrent use of warfarin with fluoxetine. If these drugs must be administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if fluoxetine is added to or removed from the regimen of a patient stabilized on warfarin. Both fluoxetine and warfarin have been associated with bleeding; coadministration may further increase the risk for bleeding. Fluoxetine may potentiate the hypoprothrombinemic effects of warfarin, perhaps by inhibiting warfarin's CYP2C9 metabolism. In addition, because fluoxetine is highly bound to plasma protein, coadministration with warfarin (another drug that is highly bound to protein) may cause an increase in warfarin plasma concentrations. Cases of enhanced warfarin effect have been reported. SSRIs like fluoxetine can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding; however, the absolute risk is not known. Fluoxetine; Olanzapine: If possible, avoid concurrent use of warfarin with fluoxetine. If these drugs must be administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if fluoxetine is added to or removed from the regimen of a patient stabilized on warfarin. Both fluoxetine and warfarin have been associated with bleeding; coadministration may further increase the risk for bleeding. Fluoxetine may potentiate the hypoprothrombinemic effects of warfarin, perhaps by inhibiting warfarin's CYP2C9 metabolism. In addition, because fluoxetine is highly bound to plasma protein, coadministration with warfarin (another drug that is highly bound to protein) may cause an increase in warfarin plasma concentrations. Cases of enhanced warfarin effect have been reported. SSRIs like fluoxetine can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding; however, the absolute risk is not known. Fluoxymesterone: Androgens are associated with potentiation of the hypoprothrombinemic effect of warfarin. These interactions have resulted in bleeding episodes in some patients receiving coumarin derivatives along with danazol, esthylestrenol, methyltestosterone, oxandrolone, oxymetholone, or stanozolol. A multidose study of oxandrolone in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80-85% dose reduction) was necessary to maintain a target INR of 1.5. When oxandrolone is prescribed to patients being treated with warfarin, doses of warfarin may need to be decreased significantly to maintain a desirable INR level and diminish the risk of potentially serious bleeding. A case report describes an increased INR in a woman receiving topical testosterone propionate ointment and anticoagulation with warfarin. In addition, danazol and stanozolol (androgen-related compounds), are associated with potentiation of the hypoprothrombinemic effect of warfarin. Danazol may inhibit warfarin metabolism and/or may potentiate the anticoagulant effects by affecting the coagulation system, and has been associated with reports of serious bleeding events. When androgen therapy is initiated in a patient already receiving warfarin, the patient should be closely monitored with frequent evaluation of the INR and clinical parameters; the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen or androgen-related (danazol, stanozolol) therapy is changed or discontinued. Flurbiprofen: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Flutamide: Prothrombin times and/or INRs have increased in patients receiving long-term warfarin therapy who are given flutamide. Adjustment of the warfarin dose may be required during flutamide therapy. Fluvastatin: Bleeding and/or increased prothrombin times have been reported in patients taking HMG-CoA reductase inhibitors and coumarin anticoagulants together; monitor the anticoagulant effects of warfarin very carefully any time fluvastatin is either initiated or discontinued during warfarin therapy. Several case reports have shown that stabilized warfarin doses needed to be decreased after the addition of fluvastatin. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin. According to the manufacturer, concomitant administration of a single dose of warfarin (30 mg) in young healthy males receiving immediate-release fluvastatin (40 mg/day for 8 days) resulted in no elevation of racemic serum warfarin concentrations. There was also no effect on prothrombin complex activity with coadministration of warfarin with fluvastatin versus placebo. Fluvoxamine: If possible, avoid concurrent use of warfarin with fluvoxamine. If these drugs must be administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if fluvoxamine is added to or removed from the regimen of a patient stabilized on warfarin. Fluvoxamine is a potent inhibitor of CYP1A2 and thus may inhibit the metabolism of warfarin via this enzyme. According to a manufacturer-based study, fluvoxamine increased warfarin serum concentrations by 98%, resulting in a prolonged INR; in clinical use case reports of bleeding or enhanced warfarin effect have been reported. Fluvoxamine may potentiate the hypoprothrombinemic effects of warfarin, perhaps by inhibiting platelet aggregation. SSRIs like fluvoxamine can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding; however, the absolute risk is not known. Folate analogs: Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Folic Acid, Vitamin B9: L-methylfolate and warfarin should be used together cautiously. Significant impairment of folate status may occur after 6 months of therapy with warfarin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together. Fondaparinux: There have been no documented pharmacokinetic interactions of fondaparinux with warfarin. However, an additive risk of bleeding may be seen in patients receiving warfarin in combination with fondaparinux. If possible, agents that enhance the risk of bleeding should be discontinued prior to initiation of fondaparinux therapy. Food: Interactions with warfarin and cranberry juice (cranberry, Vaccinium macrocarpon Ait.) have been reported, but the data are controversial. Some case reports have reported increased INR or other clinically significant events, while limited and small controlled clinical research data do not support an interaction. It is not clear if warfarin would interact with cranberry supplements (e.g., dried extracts); caution is advised until further data are available; patients should likely have consistent cranberry intake, including intake of cranberry capsules and concentrates, if on warfarin therapy. Phytonadione, vitamin K1, is a pharmacologic antagonist of warfarin; it is often administered to reverse elevated INR from warfarin overdose. Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin. Response to warfarin usually returns after stopping the vitamin K-containing product. Occult sources of vitamin K include enteral feedings, certain multivitamins, and many food products. Foods that contain large amounts of vitamin K include green tea, brussel sprouts, and kale. Other foods that contain moderate-high quantities of vitamin K include asparagus, avocado, broccoli, cabbage, cauliflower, collard greens, lettuce, liver, soy products (including soy milk, soybeans or soybean oil), lentils, peas, mustard greens, turnip greens, parsley, green scallions, and spinach. Medical products that contain soybean oil such as intravenous lipid emulsions or propofol, may decrease warfarin anticoagulation. Intravenous lipids may interfere with warfarin anticoagulation in many ways including enhancing the production of clotting factors, facilitating platelet aggregation, supplying vitamin K, and enhancing warfarin binding to albumin. In general, it is recommended that patients avoid large servings or frequent intake of foods that contain substantial amounts of vitamin K. Use caution in combining marijuana use with warfarin. CYP2C9 is the principle enzyme that metabolizes S-warfarin and modulates the in vivo activity of warfarin. Certain cannabinoids in marijuana may inhibit CYP2C metabolism. Avoid use of marijuana in patients on warfarin therapy when possible. If co-use cannot be avoided, the international normalized ration (INR) should be carefully monitored. A case report noted an enhanced effect of warfarin, resulting in an elevated INR and associated bleeding, when a patient increased her ingestion of chamomile tea (chamomile, Matricaria recutita); this is the only known formal report of an interaction. Various chamomile species are known to contain coumarin related compounds that are postulated to have an additive effect with warfarin, but mechanisms have not been precisely determined. The authors recommend that patients limit and not greatly alter their chamomile use while taking warfarin therapy. Dietary intake and dietary supplements may affect the response to warfarin therapy. Educate patients on the potential risks of dietary extremes and the ingestion of nutritional supplements, and the importance of dietary balance. Monitor the patient clinically for adverse events and via appropriate and regular monitoring of the INR. Fosamprenavir: Many antiretroviral agents may interact with warfarin. Agents that inhibit cytochrome P450 (CYP) isoenzymes 3A4, 1A2, or 2C9 may decrease the metabolism of warfarin leading to increased anticoagulation effects. Interactions may occur when warfarin is given with anti-retroviral protease inhibitors. Ritonavir may have induction or inhibition affects on warfarin metabolism. When warfarin (single dose of 5 mg) is administered with ritonavir (400 mg every 12 hours) a 9% increase in warfarin AUC and a 9% decrease in warfarin Cmax is seen. The high vitamin E content in amprenavir formulations may exacerbate the effects of warfarin. Patients should be carefully monitored for changes in INR, with the potential need for warfarin dosage adjustments, if warfarin and antiretroviral agents are coadministered. Fosinopril; Hydrochlorothiazide, HCTZ: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Fulvestrant: Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients. Furosemide: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Gallium Ga 68 Dotatate: Per the prescribing information for warfarin sodium, concomitant use of diuretics, including osmotic diuretics like mannitol, and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Garlic, Allium sativum: Garlic produces clinically significant antiplatelet effects so additive bleeding may occur if anticoagulants are given in combination with garlic, allium sativum. In regard to warfarin, no substantial clinical data are available to support or deny a potential for interaction; the data are limited to a random case report. A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints. Gefitinib: Monitor INR regularly and watch carefully for signs and symptoms of bleeding if gefitinib and warfarin are used concomitantly. Elevated INR and/or hemorrhage have been reported in some patients taking warfarin while on gefitinib therapy. At high concentrations, gefitinib is an inhibitor of CYP2D6 and CYP2C19, which are partially responsible for the metabolism of warfarin. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily). Gemcitabine: An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. Gemfibrozil: Use caution if warfarin is coadministered with gemfibrozil. Reduce the dose of warfarin to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequently monitor prothrombin until it has been definitely determined that the prothrombin level has stabilized. Gemtuzumab Ozogamicin: Due to the thrombocytopenic effects of gemtuzumab ozogamicin, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Gentamicin: The concomitant use of warfarin with many classes of antibiotics, including aminoglycosides, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Ginger, Zingiber officinale: Additive bleeding may occur if anticoagulants are given in combination with ginger, zingiber officinale. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist. Patients taking ginger and an anticoagulant should be monitored closely for bleeding. Ginkgo, Ginkgo biloba: Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants. Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants (e.g., warfarin), aspirin, ASA or other platelet inhibitors, or thrombolytic agents. A patient who had been taking aspirin 325 mg/day PO for 3 years following coronary-artery bypass surgery, developed spontaneous bleeding into his eye after taking a standardized extract of Ginkgo biloba (Ginkoba commercial product) 40 mg PO twice daily for one week. The patient stopped taking the ginkgo but continued taking the aspirin with no recurrence of bleeding over a 3-month period. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic ginkgo biloba ingestion. Ginseng, Panax ginseng: Interactions have been reported clinically between ginseng and warfarin. With regard to warfarin, one case report is noted of a decreased INR (reduced anticoagulant effect) after the addition of ginseng (Ginsana) in a patient stabilized on warfarin, followed by a return to the desired INR after ginseng was discontinued. In another report, ginseng was implicated in a life-threatening case of valve thrombosis in a patient with an inability to maintain a therapeutic INR on warfarin after he began using a commercial ginseng product. The effect of ginseng on warfarin has been evaluated in a double-blind, placebo-controlled trial of 4 weeks duration in healthy volunteers. The subjects (n= 20) received warfarin (5 mg/day PO x 3 days/week). Beginning in week two, 12 of the subjects took ginseng powder (2 g/day PO in capsules); 8 subjects took placebo capsules. Compared with the placebo group, the ginseng group had significantly reduced INR values, warfarin AUCs, and peak plasma warfarin concentrations after 2 weeks. Concurrent use of ginseng and warfarin is not recommended; clinicians should discuss ginseng use with patients. Ginseng (Panax ginseng) also exerts antiplatelet activity and theoretically may interact with other drugs that exhibit antiplatelet effects or anticoagulant activity; however, data are not available to confirm or deny clinical interactions. Glucagon: Glucagon has been reported to enhance the hypoprothrombinemic response in 8 out of 13 patients receiving warfarin. Clinical bleeding also was reported in 3 patients. These findings - based on data from only 13 patients - were published in 1970 and no subsequent reports have been identified. The mechanism of this interaction is uncertain. Glucosamine: Case reports have reported a possible interaction between chondroitin; glucosamine and warfarin or other coumarin anticoagulants, resulting in an increase in INR and a need for warfarin dosage adjustment. In one case report, the patient was taking twice the recommended dosage of a popular chondroitin; glucosamine supplement (Cosamin DS). Controlled clinical trials of chondroitin; glucosamine for the treatment of osteoarthritis have not reported drug interactions with oral anticoagulants at typical dosages of up to 1500 mg glucosamine; 1200 mg chondroitin/day PO. However, drug interactions with these supplements have not been specifically studied. Until more is known regarding the potential for chondroitin or glucosamine to interact with warfarin, it may be prudent to closely monitor patients stabilized on warfarin if these dietary supplements are added to their therapy regimen. Glycylcyclines: In healthy subjects receiving tigecycline (repeated dosing) and warfarin (25 mg single dose) concomitantly, the clearance of R-warfarin and S-warfarin was decreased by 40% and 23%, the Cmax increased by 38% and 43%, and the AUC increased by 68% and 29%, respectively. Tigecycline did not significantly alter the effects of warfarin on the INR in this single-dose study. Warfarin did not affect the pharmacokinetic profile of tigecycline. However, it is recommended that the prothrombin time or other suitable anticoagulation test (i.e., INR) be monitored if tigecycline is administered with warfarin. Golimumab: The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during golimumab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as warfarin. If golimumab is initiated or discontinued in a patient taking warfarin, check the INR; warfarin dose adjustment may be needed. Green Tea: Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin, and others) thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, cilostazol and others). Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with any of these agents. Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin; stability of the diet can be an important factor in maintaining anticoagulation goals. Occult sources of vitamin K include green tea and green tea dietary supplements. Published data are limited in regard to this interaction. A patient with previous INRs of 3.2. and 3.79 on a dose of 7.5mg daily of warfarin (goal INR 2.5 to 3.5) had an INR of 1.37. One month later, the patient's INR was 1.14. The patient admitted that he had started consuming 0.51 gallon of green tea daily approximately one week prior to the INR of 1.37. The patient denied noncompliance and other changes in diet, medications, or health. The patient discontinued green tea and one week later his INR was 2.55. While the amount of vitamin K in a single cup of brewed green tea may not be high (0.03 mcg/100 g), the actual amount may vary from cup to cup depending on the amount of tea leaves used, the length of time the tea bags are allowed to brew, and the volume of tea consumed. Additionally, if a patient drinks multiple cups of tea per day, the amount of vitamin K could reach significance. It is recommended that patients on warfarin maintain a stable intake of green tea. Griseofulvin: The anticoagulant effect of warfarin can be decreased if griseofulvin is used concurrently. The griseofulvin-warfarin drug interaction is one of the most well-documented warfarin drug interactions. The mechanism of this interaction is unclear. It is commonly believed that griseofulvin enhances the hepatic metabolism of warfarin. The interaction between warfarin and griseofulvin may require up to 12 weeks to fully manifest and may be more significant with the ultramicrocrystalline formulation of griseofulvin. The international normalized ratio (INR) should be monitored closely if griseofulvin is either added to or discontinued from warfarin therapy. Guarana: Guarana has been shown to possess minor antiplatelet activity and, therefore, concurrent use of guarana and anticoagulants or platelet inhibitors should be avoided. Haloperidol: Haloperidol can decrease the anticoagulation effects of warfarin. If these drugs are coadministered, monitor INR and adjust warfarin doses as needed. Halothane: Halothane can increase the effects of warfarin, although the clinical significance of this interaction is not clear. Hemin: Because hemin has exhibited transient, mild anticoagulant effects during clinical studies, concurrent use of anticoagulants should be avoided. The extent and duration of the hypocoagulable state induced by hemin has not been established. Heparin: An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with heparin. Heparin and warfarin therapies often overlap with no serious sequelae, although the risk of bleeding is nonetheless increased. It should be noted that heparin also can prolong prothrombin time. When heparin and warfarin are administered concomitantly, wait at least 5 hours after the last IV heparin dose or 24 hours after the last subcutaneous heparin dose before drawing blood to obtain prothrombin time. Hydantoins: The interaction between warfarin and phenytoin is very complex. An immediate interaction may occur as phenytoin can displace warfarin from protein binding sites causing rapid increases in the INR. After prolonged administration, phenytoin may reduce the effectiveness of warfarin by inducing the metabolism of warfarin. Competitive inhibition may also occur since phenytoin and warfarin are both substrates for cytochrome P450 2C9. Phenytoin also may deplete vitamin-K dependent clotting factors after prolonged therapy. Warfarin dosage adjustments may be necessary if phenytoin is added. Warfarin may alter phenytoin serum concentrations as well. Similar interactions with warfarin would be expected with fosphenytoin and ethotoin. Oral anticoagulant dosage adjustments may also be necessary on discontinuation of the anticonvulsant. Hydralazine; Hydrochlorothiazide, HCTZ: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ; Irbesartan: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ; Lisinopril: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ; Losartan: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ; Methyldopa: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Per the prescribing information for warfarin sodium, the concomitant use of methyldopa with warfarin has been associated with elevations in the INR. Patients should be monitored for changes in the INR when methyldopa is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ; Metoprolol: Per the prescribing information for warfarin sodium, concomitant use of beta-blockers and warfarin may result in elevations in PT/INR response. As propranolol has been shown to increase warfarin AUC and concurrent increases in INR values have been reported, patients receiving warfarin should be monitored for changes in the INR when beta-blockers are initiated or discontinued, or if the dosage is changed. Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ; Moexipril: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ; Olmesartan: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ; Propranolol: Propranolol has been shown to increase warfarin AUC, and concurrent increases in INR values have been reported. Patients should be monitored for changes in anticoagulation parameters during concurrent therapy with propranolol and warfarin. Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ; Quinapril: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ; Spironolactone: Spironolactone has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed. Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ; Telmisartan: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. The coadministration of telmisartan and warfarin may lead to a decrease in the anticoagulation effects of warfarin. Hydrochlorothiazide, HCTZ; Triamterene: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrochlorothiazide, HCTZ; Valsartan: Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Hydrocodone; Ibuprofen: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Hydrocortisone; Lidocaine: Psyllium can interfere with the absorption of certain oral drugs if administered concomitantly. For example, psyllium fiber is theorized to adsorb oral anticoagulants (e.g., warfarin); although, response to a single dose of warfarin was not affected by repeated administration (every 2 hours) of psyllium in a group (n=6) of healthy subjects. Per the psyllium manufacturers, administration of other prescribed oral drugs should be separated from the administration of psyllium by at least 2 hours. Hydroxyurea: An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly. Ibritumomab Tiuxetan: Due to the thrombocytopenic effects of the ibritumomab tiuxetan therapeutic regimen, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Ibrutinib: Use caution with concomitant use of ibrutinib and anticoagulants such as warfarin. Bleeding or bruising events occurred in 48 to 63% (grade 3 or 4, 5 to 6%) of patients treated with ibrutinib in clinical trials. The mechanism for bleeding is not well understood, and the risk of hemorrhage may be increased in patients receiving anticoagulant therapy. Closely monitor patients for signs ans symptoms of bleeding. Ibuprofen lysine: Because ibuprofen can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time, additive pharmacodynamic effects may be seen in patients receiving anticoagulants. Ibuprofen: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Ibuprofen; Oxycodone: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Ibuprofen; Pseudoephedrine: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Icosapent ethyl: Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly. Idelalisib: Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with warfarin, a CYP3A substrate, as warfarin toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. In addition, the use of warfarin in patients with blood dyscrasias is contraindicated. Therefore, to minimize the bleeding risk, warfarin should be used cautiously in patients receiving antineoplastic agents that cause myelosuppression or blood dyscrasias. In addition, effects of antineoplastic agents on protein synthesis as well as protein binding may lead to transient changes in a patient's INR while receiving warfarin. The INR may increase and/or decrease throughout the chemotherapy cycle leading to supra- or sub-therapeutic values; monitor warfarin therapy closely. Ifosfamide: Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Iloprost: When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding. Imatinib, STI-571: Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, as well as thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. The manufacturer recommends that patients who require anticoagulation while receiving imatinib should receive low-molecular weight heparin or standard heparin instead of warfarin. Coagulation parameters should be monitored closely if warfarin therapy is continued during imatinib therapy. Imatinib is a potent inhibitor of cytochrome P450 (CYP) 3A4 and CYP2C9, and therefore has potential to increase serum concentrations of warfarin. Since both imatinib and warfarin are highly protein bound (95% and 99%, respectively), displacement from plasma proteins may also occur. In a phase II trial of imatinib, a patient with Philadelphia positive chronic myelogenous leukemia in chronic phase developed cerebral and urinary tract bleeding while receiving imatinib 400 mg daily in combination with warfarin (dose not available). Although a significantly prolonged prothrombin time may have been the result of an increase in the patient's warfarin dose in the days preceding the bleeding, a drug interaction cannot be excluded. Imipenem; Cilastatin: The concomitant use of warfarin with many classes of antibiotics, including carbapenems, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. Indapamide: Per the prescribing information for warfarin sodium, concomitant use of diuretics, including indapamide, and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed. Indinavir: Many antiretroviral agents may interact with warfarin. Agents that inhibit cytochrome P450 (CYP) isoenzymes 3A4, 1A2, or 2C9 may decrease the metabolism of warfarin leading to increased anticoagulation effects. Interactions may occur when warfarin is given with anti-retroviral protease inhibitors. Ritonavir may have induction or inhibition affects on warfarin metabolism. When warfarin (single dose of 5 mg) is administered with ritonavir (400 mg every 12 hours) a 9% increase in warfarin AUC and a 9% decrease in warfarin Cmax is seen. The high vitamin E content in amprenavir formulations may exacerbate the effects of warfarin. Patients should be carefully monitored for changes in INR, with the potential need for warfarin dosage adjustments, if warfarin and antiretroviral agents are coadministered. Indomethacin: An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. The Beers criteria recommends avoiding this combination in older adults; if the combination cannot be avoided, monitor closely for evidence of bleeding. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2 mg to 5 mg daily, the INR was unaffected by the addition of celecoxib. Infliximab: The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during infliximab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as warfarin. If infliximab is initiated or discontinued in a patient taking warfarin, check the INR; warfarin dose adjustment may be needed. Interferon Alfa-2a: An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. Interferon Alfa-2b: An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. Interferon Alfa-2b; Ribavirin: An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. Interferon Alfacon-1: An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants. Isavuconazonium: Concomitant use of isavuconazonium with warfarin may result in increased serum concentrations of warfarin and an increased risk of bleeding. Warfarin is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together. Isoniazid, INH: Isoniazid, INH, can inhibit the hepatic oxidative metabolism of warfarin. Alterations in the effects of warfarin may occur if isoniazid is added or discontinued. This interaction may be dose-dependent; a significant interaction with warfarin occurs at INH doses of 600 mg/day but not necessarily at INH doses of 300 mg/day. Isoniazid, INH; Pyrazinamide, PZA; Rifampin: Isoniazid, INH, can inhibit the hepatic oxidative metabolism of warfarin. Alterations in the effects of warfarin may occur if isoniazid is added or discontinued. This interaction may be dose-dependent; a significant interaction with warfarin occ